Huntington's disease (HD) is a devastating autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion encoding an abnormally long polyglutamine tract in the huntingtin protein. Much has been learnt since the mutation was identified in 1993. We review the functions of wild-type huntingtin. Mutant huntingtin may cause toxicity via a range of different mechanisms. The primary consequence of the mutation is to confer a toxic gain of function on the mutant protein and this may be modified by certain normal activities that are impaired by the mutation. It is likely that the toxicity of mutant huntingtin is revealed after a series of cleavage events leading to the production of N-terminal huntingtin fragment(s) containing the expanded polyglutamine tract. Although aggregation of the mutant protein is a hallmark of the disease, the role of aggregation is complex and the arguments for protective roles of inclusions are discussed. Mutant huntingtin may mediate some of its toxicity in the nucleus by perturbing specific transcriptional pathways. HD may also inhibit mitochondrial function and proteasome activity. Importantly, not all of the effects of mutant huntingtin may be cell-autonomous, and it is possible that abnormalities in neighbouring neurons and glia may also have an impact on connected cells. It is likely that there is still much to learn about mutant huntingtin toxicity, and important insights have already come and may still come from chemical and genetic screens. Importantly, basic biological studies in HD have led to numerous potential therapeutic strategies.

INTRODUCTION

Huntington's disease (HD) is a devastating autosomal dominant neurodegenerative disorder named after George Huntington, who provided a classic account of the condition in 1872 in The Medical and Surgical Reporter [1]. However, the first definite description of HD by Charles Oscar Waters in 1841 provides a lucid picture of one of its main clinical features, chorea, and its hereditary nature [2]: “It consists essentially in a spasmodic action of all the voluntary muscles of the system, of involuntary and more or less irregular motions of the extremities, face and trunk… The disease is markedly hereditary… The first indications of its appearance are spasmodic twitching of the extremities, generally of the fingers which gradually extend and involve all the involuntary muscles. This derangement of muscular action is by no means uniform; in some cases it exists to a greater, in others to a lesser, extent, but in all cases gradually induces a state of more or less perfect dementia. When speaking of the manifestly hereditary nature of the disease, I should perhaps have remarked that I have never known a case of it to occur in a patient, one or both of whose ancestors were not, within the third generation at farthest, the subject of this distressing malady…”

Although Waters stated that “the singular disease rarely, very rarely indeed, makes its appearance before adult life, and attacks after the age of 45 are also very rare”, this reflects the peak of the incidence distribution, since HD can present at any age.

The pathology of HD reveals striking neurodegeneration in the corpus striatum and shrinkage of the brain. These features were initially described by Meynert (1877) [3] and Jelgersma (1907) [4]. The obvious loss of the caudate and putamen (corpus striatum) has led to the widely held belief that these neurons are most vulnerable to the mutation and also that loss of these specific neuronal populations can account for the motor, psychiatric and cognitive features of disease. More recent studies suggest that there is also widespread cortical loss/dysfunction in early HD [5]. This raises the possibility that some of the features of HD may be driven by cortical dysfunction and the speculation that some of the striatal loss may be a secondary consequence of perturbations to cortico–striatal pathways.

GENETICS OF HD

The gene responsible for HD (HTT) was discovered in 1993 and encodes a 350 kDa ubiquitously expressed protein called huntingtin [6]. The causative mutation is an abnormal expansion of a tract of uninterrupted CAG trinucleotide repeats within the coding sequence of the gene, 17 codons downstream of the initiator ATG codon in exon 1. CAG is a codon for glutamine, and the mutation leads to an abnormally expanded polyglutamine tract in huntingtin [6]. There are now nine diseases that are known to be caused by expanded CAG-encoded polyglutamine tracts, including many of the dominant SCAs (spinocerebellar ataxias): SCA1, 2, 3, 6, 7 and 17.

In normal individuals, the number of CAG repeats is 35 or fewer, with 17–20 repeats found most commonly [7]. Repeats between 27 and 35 are rare and are not associated with disease, but are meiotically unstable and can expand into the disease range of 36 and above, when transmitted through the paternal line. Most adult-onset cases have 40–50 CAGs, whereas expansions of 50 and more repeats generally cause the juvenile form of the disease. Incomplete penetrance has been observed in individuals with 36–41 repeats, but the estimates of penetrance for this group are imprecise [8,9].

There is a strong inverse relationship between the age of onset of HD and the number of CAG repeats. Longer repeats are correlated with an earlier age of onset [10]. However, there is a wide variation in the age of onset with a given CAG repeat number, and the CAG repeat number itself has poor predictive power on the age of onset for any given individual. Only approx. 70% of the variance in the age of onset of HD can be accounted for by the number of CAG repeats. The residual variance is represented by other modifying genes and environmental factors [1118].

Many trinucleotide-repeat disorders, including HD, are characterized by the phenomenon of anticipation, where the age of onset decreases and the disease severity increases in successive generations. This phenomenon can be explained by meiotic instability (which increases the number of CAG repeats) that appears to be greater in spermatogenesis than oogenesis; anticipation is mainly observed when the mutation is inherited through the paternal line [1921].

In contrast with some of the inherited dominant ataxias where the clinical course is more severe in homozygotes [22], HD was previously believed to be one of the rare genetic diseases which demonstrated ‘complete dominance’, i.e. heterozygotes were as badly affected as homozygotes. However, more recent clinical and molecular studies have suggested that, although homozygosity for the HD mutation does not influence the age of onset of symptoms, homozygosity is associated with a more aggressive disease course [23,24].

GENETIC MECHANISM OF ACTION OF THE CAG MUTATION

Genetic data in humans and transgenic animal models suggest that polyglutamine mutations confer a deleterious gain-of-function on the target proteins [10,25,26]. HD is an autosomal dominant condition: one mutated gene is sufficient to cause the disease, in spite of the presence of a normal gene inherited from the other parent. In humans, loss of one of the two HTT genes occurs in Wolf–Hirschorn syndrome as a result of a terminal deletion of one chromosome 4, involving the loss of one HTT gene [27], and has also occurred with a balanced translocation with a breakpoint between exons 40 and 41 which physically disrupts the HTT gene [28]. Hemizygous inactivation of huntingtin does not cause an abnormal HD-like phenotype. In addition, mice with only one functioning Htt gene do not show features of the disease [2931].

Gain-of-function is also suggested by studies showing that the expanded CAG repeat is toxic itself. Expression of expanded polyglutamine peptides alone in Drosophila models has been shown to cause neurodegeneration [32]. Ordway et al. [33] created a mouse model where a 146 CAG repeat sequence was inserted into the hypoxanthine phosphoribosyltransferase (Hprt) gene, which is not involved in any CAG-repeat disorders, and inactivation of the Hprt gene alone does not have any deleterious effects in mice. These mutant mice produced a polyglutamine-expanded form of the hypoxanthine phosphoribosyltransferase protein and developed a late-onset neurological phenotype that progressed to premature death [33]. Transgenic overexpression of polyglutamine expansions, either in the context of the full-length huntingtin protein or only exon 1 of Htt, also produce neurodegeneration in mice and Drosophila [34]. Although the primary consequence of the HD mutation is to confer gain-of-function, this does not preclude the possibility that disease severity may be modified by certain loss-of-function effects [35].

HUNTINGTIN

Wild-type huntingtin is found mostly in the cytoplasm, although a small proportion of the protein is intranuclear [37]. The protein is known to be associated with the plasma membrane, endocytic (both clathrin-coated and non-coated) and autophagic vesicles, endosomal compartments, the ER (endoplasmic reticulum), the Golgi apparatus, mitochondria and microtubules [3742].

Although the polyglutamine repeat in huntingtin has received attention for its pathogenic properties when expanded, it is possibly not essential for normal function [4345]. Another feature of huntingtin protein structure is the presence of multiple HEAT (huntingtin, elongation factor 3, the PR65/A subunit of protein phosphatase 2A and the lipid kinase Tor) repeat sequences; 28–36 of these motifs are predicted to be distributed along the entire length of the huntingtin protein [46,47] (Figure 1). A HEAT repeat is a degenerate ∼50-amino-acid sequence comprising two anti-parallel α-helices forming a hairpin. HEAT motifs are usually involved in protein–protein interactions and are found in proteins that often play roles in intracellular transport (including nucleocytoplasmic shuttling), microtubule dynamics and chromosome segregation. These proteins are also characterized by high helical content (>50%) and frequently form superhelical structures with continuous hydrophobic cores [4850]. Indeed, characterization of full-length huntingtin by biophysical methods suggests that the protein is an elongated superhelical solenoid with a diameter of ∼200 Å (1 Å=0.1 nm) [46].

Huntingtin and its normal cellular roles

Figure 1
Huntingtin and its normal cellular roles

(A) Linear structure of the huntingtin molecule. The locations of the main huntingtin polypeptide sequence features are shown, including the polyglutamine (polyQ) and polyproline (polyP) sequences, NES and clusters of HEAT motifs (blue bars). Sites of post-translational modifications such as ubiquitination, SUMOylation, palmitoylation, phosphorylation and cleavage by proteases are also shown. (B) Probable three-dimensional structure of huntingtin as an elongated superhelical solenoid containing multiple HEAT repeats. The structure has been modelled on another HEAT repeat protein that has a molecular mass similar to that of huntingtin [47]. (C) Proposed cellular functions of wild-type huntingtin. Relevant interacting partners of huntingtin are shown in yellow. See the text for details.

Figure 1
Huntingtin and its normal cellular roles

(A) Linear structure of the huntingtin molecule. The locations of the main huntingtin polypeptide sequence features are shown, including the polyglutamine (polyQ) and polyproline (polyP) sequences, NES and clusters of HEAT motifs (blue bars). Sites of post-translational modifications such as ubiquitination, SUMOylation, palmitoylation, phosphorylation and cleavage by proteases are also shown. (B) Probable three-dimensional structure of huntingtin as an elongated superhelical solenoid containing multiple HEAT repeats. The structure has been modelled on another HEAT repeat protein that has a molecular mass similar to that of huntingtin [47]. (C) Proposed cellular functions of wild-type huntingtin. Relevant interacting partners of huntingtin are shown in yellow. See the text for details.

It is unknown whether huntingtin contains NLSs (nuclear localization signals). However, a conserved NES (nuclear export signal) is found near its C-terminus [51]. In addition, the N-terminal 17-amino-acid sequence of huntingtin has been suggested to act as a NES owing to its binding to the nuclear exporter Tpr (translocated promoter region). Expansion of the polyglutamine repeat interferes with this interaction causing accumulation of mutant huntingtin in the nucleus [51,52]. The 17-amino-acid N-terminal stretch of huntingtin has been recognized as playing an important role, together with a cluster of the first three HEAT repeats flanked by positively charged regions (amino acids residues 172–372), in targeting huntingtin to various intracellular membrane-bound organelles, including the plasma membrane, mitochondria, endosomal/autophagic vesicles, the Golgi apparatus and the ER [38,41,42]. Finally, several lysine residues within the same 17-amino-acid sequence immediately before the polyglutamine repeat, appear to compete for SUMOylation and ubiquitination, post-translational modifications that could regulate the half-life, localization and nuclear export of wild-type huntingtin, as well as modifying the toxicity of the mutant protein [5355].

Cys214 of huntingtin is palmitoylated by Hip (huntingtin-interacting protein) 14, a palmitoyltransferase that regulates trafficking and function of huntingtin as well as several other neuronal proteins [56,57]. Palmitoylation could potentially play a role in the development of pathology as huntingtin with an expanded polyglutamine repeat is a much poorer Hip14 substrate compared with wild-type protein [57].

Both wild-type and mutant huntingtin are cleaved by various intracellular proteases, including caspases 1, 3, 6, 7 and 8, calpain and an unidentified aspartic protease [5862]. Although the importance of huntingtin proteolysis for its physiological function remains to be elucidated, the role of mutant huntingtin cleavage in the progress of the disease is well established, as the full-length mutant protein is less toxic than its N-terminal fragments [63,64] (see below).

HUNTINGTIN, A PLAYER OF MANY GAMES

Despite substantial efforts directed towards understanding huntingtin function during last 14 years, its normal cellular roles remain poorly defined. This is predominantly due to the large size of the protein that makes isolation and analysis difficult, the lack of obvious homology with other proteins, ubiquitous localization within the cell and promiscuous interactions with more than 200 partners identified to date [43,44,65,66].

We will briefly describe several of the most well-studied cellular roles attributed to huntingtin (also see Figure 1). Although these diverse functions are currently considered to be relatively independent of each other, this view may change with an advancement of our knowledge about this interesting protein. Already, huntingtin is beginning to emerge as a scaffold protein orchestrating converging intracellular trafficking and signalling pathways.

Huntingtin is essential for normal embryonic development, as the loss of protein causes increased apoptosis and disrupted transport of maternal nutrients into the fetus, leading to lethality of mouse embryos around day 8.5 [2931]. Knockdown of huntingtin expression in zebrafish embryos also produces a variety of developmental defects, including disruption of iron homoeostasis [67]. In addition, the protein is required in adult neurons and testis for cellular viability [68]. The high levels of cell death in HTT-knockout animals suggests that the protein may have an anti-apoptotic role [31]. This idea is supported by the observations that overexpression of wild-type huntingtin protects against various apoptotic insults including those caused by starvation, mitochondrial toxins and overexpression of mutant huntingtin with an expanded polyglutamine repeat [6971]. One possible molecular explanation for the anti-apoptotic capability of wild-type huntingtin is that it binds and sequesters the pro-apoptotic protein Hip1 that together with HIPPI (Hip1 protein interactor) can activate pro-caspase 8 [72]. Also, huntingtin may also inhibit caspase 3 directly [73].

Huntingtin is involved in transcription regulation by interacting with an array of transcriptional factors and other proteins involved in the regulation of mRNA production [43,44,65,66]. Huntingtin has also been shown to interact with tryptophan (WW) domain-containing proteins implicated in non-receptor signalling and pre-mRNA splicing [74]. On the basis of this, and by analogy with other HEAT domain-containing proteins (e.g. importins) that interact with transcriptional regulatory proteins and facilitate their transport between cytoplasm and nucleus, huntingtin has a proposed role in nucleocytoplasmic shuttling of transcriptional regulators and mRNA [47,51,75]. However, this function of wild-type huntingtin remains largely speculative, as most research has focused so far on the perturbations of transcriptional activity by mutant huntingtin. The most well-established example of huntingtin functioning as a transcriptional regulator is its role in the production of BDNF (brain-derived neurotrophic factor), which does not require the nuclear translocation of huntingtin and is performed in the cytosol. In this case, huntingtin binds and sequesters REST (repressor element-1 silencing transcription factor)/NRSF (neuron-restrictive silencer factor), a transcription factor that binds to NRSE (neuron-restrictive silencer element), an upstream DNA element found in ∼2000 genes including BDNF. Thus huntingtin acts as a positive transcriptional regulator of NRSE-regulated genes such as BDNF [76].

The role of huntingtin in vesicle trafficking was originally proposed on the basis of its localization to endocytic/endosomal vesicles in axons and synaptic terminals and from its interaction with a number of endocytic/trafficking proteins, including α-adaptin, Hip1, Hip14, Hap (huntingtin-associated protein) 1, Hap40, PACSIN1 (protein kinase C and casein kinase substrate in neurons-1) and SH3GL3 [SH3 (Src homology 3)-domain Grb2-like 3] (endophilin 3) (reviewed in [43,44,66,77]). Recently, this list has been extended to bona fide endocytic proteins, such as clathrin and dynamin [65]. However, the role of huntingtin in endocytosis, despite being proposed by many, remains elusive, as the effect of huntingtin knockdown on the endocytosis of plasma membrane receptors has yet to be shown.

In contrast, the function of huntingtin as a facilitator of long- and short-range transport along microtubules is documented in mammalian cells, Drosophila and mouse models [39,7881]. Huntingtin interacts directly, as well as via its binding partner Hap1, with the dynein/dynactin microtubule-based motor complex responsible for retrograde cellular trafficking. In addition, Hap1 binds another molecular motor, kinesin, and thus could play a role (independently or as part of a complex with huntingtin) in anterograde axonal transport. Huntingtin in complex with another partner Hap40 was shown to be important for movement of Rab5-positive endosomes along microtubules. As a result, knockdown of huntingtin inhibits movement of vesicles and mitochondria along neuronal projections [39,7882]. Importantly, in addition to its role in the transcriptional regulation of BDNF, huntingtin is essential for efficient axonal transport of vesicles containing this pro-survival factor and thus controls neurotrophic support and endurance of neuronal cells [78].

As discussed above, huntingtin is highly expressed presynaptically, where it interacts with many proteins involved in synaptic vesicle exocytosis and recycling [43,44,66,77]. However, with the exception of the above examples, the role of huntingtin itself in these processes remains to be established. Huntingtin also seems to be important for normal synaptic transmission as part of the protein machinery localized to PSD (postsynaptic density), an electron-dense dendritic part of the synapse. Here, huntingtin interacts directly with the SH3 domain of a key regulator of postsynaptic activity, PSD-95, which in turn forms complexes with NMDA (N-methyl-D-aspartate) and kainate receptors belonging to the family of ionotropic glutamate receptors [83]. Huntingtin was shown to negatively regulate the activity of glutamate receptors [84]. As PSD-95 is also involved in relaying the signal from glutamate receptors to proteins such as SynGAP (synaptic GTPase-activating protein), huntingtin could potentially also modulate this signal transduction thus regulating synaptic plasticity [84,85]. Finally, huntingtin has been implicated in mGluR1 (metabotropic glutamate receptor 1) signalling via its interaction with optineurin [86].

MUTANT HUNTINGTIN AND HD PATHOGENESIS

Huntingtin cleavage: a probable rate-limiting step

There is now strong support for the idea that mutant huntingtin cleavage resulting in an N-terminal fragment containing the polyglutamine expansion is a key step in pathogenesis (Figure 2). N-terminal mutant huntingtin fragments are sufficient to produce HD-like abnormal clinical syndromes in model animals [8789] and intranuclear inclusions [88,89]. Mutant huntingtin may be cleaved into a repertoire of different fragments by different proteases, including caspases, calpains and an as yet uncharacterized aspartic endopeptidase. Two cleavage sites at residues 513 and 552 are susceptible to caspase 3, producing N-terminal fragments of polyglutamine huntingtin of approx. 70 and 75 kDa respectively [90]. The cleavage site at residue 552 is also susceptible to caspase 2 [62]. A slightly larger peptide fragment, 80 kDa in size, is produced by caspase 6 cleavage at residue 586. The proteolysis and subsequent toxicity of the mutant protein can be modified (usually suppressed) as a result of phosphorylation of huntingtin by protein kinases, including Akt, Cdk5 (cyclin-dependent kinase 5) and ERK1 (extracellular-signal-regulated kinase 1) [9193]. Importantly, recent data strongly suggest that inhibition of caspase 6 cleavage of mutant huntingtin rescues both the behavioural and neuropathological HD phenotype in mice expressing full-length mutant Htt transgenes [64]. Thus the cleavage events may be rate-limiting steps in pathogenesis allowing conversion of comparatively non-toxic or benign full-length mutant huntingtin into toxic fragments.

Mutant huntingtin induces many different toxic pathways, some of which may interlink

Figure 2
Mutant huntingtin induces many different toxic pathways, some of which may interlink

For example, mutant huntingtin can be cleaved by calpains, which may result in toxic fragment production. These toxic fragments may induce excitotoxicity, which will increase intracytosolic calcium levels, which will increase calpain activity and result in further toxic fragment production. Cdk5, cyclin-dependent kinase 5; htt, huntingtin; Qn, polyglutamine.

Figure 2
Mutant huntingtin induces many different toxic pathways, some of which may interlink

For example, mutant huntingtin can be cleaved by calpains, which may result in toxic fragment production. These toxic fragments may induce excitotoxicity, which will increase intracytosolic calcium levels, which will increase calpain activity and result in further toxic fragment production. Cdk5, cyclin-dependent kinase 5; htt, huntingtin; Qn, polyglutamine.

In addition to caspases, calpains can also cleave huntingtin. The most N-terminal calpain cleavage site is at residue 536, which would lead to the formation of a 72 kDa N-terminal fragment of huntingtin as an intermediate product. This fragment may be cleaved further to generate a 47 kDa product, which is small enough in size to shuttle in and out of the nucleus [59]. Huntingtin has also been reported to be a substrate for unidentified aspartic endopeptidases [61]. This protease generates smaller N-terminal fragments of huntingtin compared with caspases and calpains and may be a crucial factor for the formation of intranuclear inclusions [61,94].

Huntingtin aggregation and its relationship with toxicity

The formation of neuronal intranuclear and intracytoplasmic inclusions of mutant huntingtin are pathological hallmarks of HD [95], and aggregates are a feature of all the known polyglutamine diseases. There has been considerable debate whether these represent toxic or protective species, or epiphenomena. In human brains, the density of inclusions in the cortex correlates with repeat length [95,96], consistent with in vitro data. However, there is little correlation between inclusion burden and the areas of the brain most affected in HD [97,98].

In mammalian cell culture systems, there is a strong correlation between aggregate formation and cellular toxicity, and cell death follows the formation of aggregates in many cases [99101]. In HD mice expressing mutant Htt exon 1, intranuclear neuronal inclusions were detected before or near the onset of behavioural changes [87,102]. Overexpression of molecular chaperone(s) including hsps (heat-shock proteins) 70, 40, 104 and the chaperonin TRiC (tail-less complex polypeptide 1 ring complex) reduced both aggregation and cell death in HD cellular and/or mouse models [100,103113]. However, these chaperones may be reducing the number of large inclusions by preventing oligomer formation, and it may be the oligomeric precursors that are the most toxic species.

Certain studies have reported a dissociation between aggregate formation and toxicity. When R6/1 HD exon 1 mice were crossed with tissue transglutaminase-knockout mice, this resulted in partial rescue of the brain and body weight loss and early mortality of the phenotype, but an increase in intranuclear inclusions [114]. Overexpression of CA150, a transcription factor, rescued neuronal toxicity, while it increased neuritic aggregation without reducing nuclear inclusions [115]. Furthermore, promotion of inclusion formation with a small molecule in a cell culture model of HD rescued huntingtin-mediated proteasome dysfunction [116]. The most striking dissociation between aggregate formation and toxicity was the demonstration that cells that formed huntingtin inclusions had an improved survival compared with those that did not form inclusions [117]. This suggests that cells with large inclusions are less compromised than cells with diffuse mutant huntingtin. However, the study did not compare the toxicity in cells with aggregates with wild-type cells. Also, cells with diffuse huntingtin are likely to contain oligomeric structures. Such oligomeric forms may be highly reactive because of their larger surface area to volume ratios, compared with large inclusions, and this may correlate with toxicity. However, in vivo, certain large inclusions may exert toxic effects if they block neuronal processes, as this may impair anterograde and retrograde transport.

PERTURBATION OF TRANSCRIPTION AS A POSSIBLE DISEASE MECHANISM

The idea that the nucleus may be an important site for huntingtin toxicity was suggested by studies proposing that the full-length wild-type protein was mainly localized to the cytosol, whereas the cleaved mutated molecule redistributed to the nuclear compartment [118]. Furthermore, nuclear localization of mutant huntingtin appeared to enhance its toxicity both in cell culture and in mice [119121]. A number of transcriptional regulators contain glutamine-rich activating domains, important for the interaction between transcription factors and transcription regulators. This led to the possibility that proteins carrying polyglutamine stretches could associate with transcription factors, leading to transcriptional alterations [122,123].

CBP [CREB (cAMP-response-element-binding protein)-binding protein] and Sp1 (specificity protein 1) have been identified as two major transcriptional regulators affected by polyglutamine proteins. CBP is an important transcription co-activator and is a major mediator of survival signals in neurons. It has histone acetyltransferase activity, which is important for allowing transcription factors access to DNA. The C-terminal glutamine-rich domain of CBP can mediate its interaction with mutated huntingtin. The interaction causes cellular toxicity and CBP relocalization from the nucleus into huntingtin aggregates [124126]. Interestingly, further studies showed that CBP–huntingtin binding is primarily mediated by CBP's acetyltransferase domain and that the interaction depends on huntingtin's polyglutamine tract and proline-rich region. Moreover, huntingtin can bind to other proteins with acetyltransferase domains, modulating their activity [127].

The connection between histone acetylation and neurodegeneration led to further investigations testing the potential of HDAC (histone deacetylase) inhibitors for therapy. In a Drosophila polyglutamine model, treatment with butyrate or SAHA (suberoylanilide hydroxamic acid) rescued neurodegeneration [127]. Similar results obtained in yeast and in cell culture provided evidence for the role of histone acetylation in neurodegeneration [128,129]. Further studies have reported beneficial effects of HDAC inhibitors in HD mouse models [130,131].

Sp1 is a sequence-specific transcription activator which binds to CG-rich regions of DNA. It contains a glutamine-rich activation domain, through which it binds to and regulates molecules of the transcriptional machinery, such as TF (transcription factor) IID, a multiprotein complex composed of TBP (TATA-box-binding protein) and multiple TAFIIs (TBP-associated factors). Moreover, Sp1 interacts with different molecules of the TFIID complex, particularly binding TAFII130 through the glutamine-rich domain, supporting the idea that the glutamine interface plays a fundamental role in recruiting components of the transcriptional machinery and subsequently RNA polymerase II [132]. A specific interaction occurs between the N-terminus of mutant huntingtin and Sp1 [133], which interferes with Sp1-driven gene regulation. Indeed, mutant huntingtin interacts with Sp1, disrupting the specific Sp1–TAFII130 complex and altering the expression of certain Sp1 neuronal target genes, including the dopamine D2 receptor [134]. Sp1–TAFII130 overexpression is able to counterbalance mutant huntingtin toxicity and suppression of dopamine D2 receptor regulation in cell culture. However, this situation may be more complex, as recent studies using cellular and transgenic HD models demonstrated that reduction of Sp1 could be neuroprotective [135]. In particular, Qui et al. [135] showed an increase in Sp1 expression levels in different experimental models of HD, suggesting that suppression of Sp1 could be beneficial for HD pathology, while an increase in Sp1 levels may enhance mutant huntingtin toxicity.

Recent studies have shown that huntingtin also interacts with members of the core transcriptional machinery other than TFIID and TFIIF, affecting gene transcription in a polyglutamine-dependent manner [136].

Another pathway by which huntingtin affects transcription regulation involves the transcriptional regulation of BDNF, which is important for the survival of striatal neurons and for the activity of cortico–striatal synapses. Studies using in vitro and in vivo models showed that wild-type huntingtin, but not the mutated form, modulates BDNF expression in the cortex by regulating its transcription. [35,137]. The expression of BDNF is regulated by REST/NRSF, which recognizes and binds to the NRSE within the BDNF promoter [138140]. Wild-type huntingtin is able to bind and sequester the cytosolic REST/NRSF, limiting its translocation to the nucleus and allowing BDNF transcription. Mutated huntingtin does not bind REST/NRSF effectively, leading to its accumulation in the nucleus. This leads to transcriptional repression of NRSE-sensitive genes, such as BDNF [76].

A new insight is emerging connecting impaired energy metabolism and transcription as contributors to HD pathology via PGC-1α (peroxisome-proliferator-activated receptor γ co-activator-1α). PGC-1α [141] is a transcriptional co-activator involved in different metabolic programmes that mainly acts as a fundamental regulator of mitochondrial biogenesis and respiration [142]. Mice lacking PGC-1α show defects in brown adipose tissue as well as a pattern of neurodegeneration not unlike that seen in HD [143,144]. The possibility that PGC-1α could have a role in HD was suggested by observations of reduced levels of PGC-1α mRNA expression in human and mouse HD brains, and experiments showing that overexpression of PGC-1α reversed the effects of mutant huntingtin in cell models and in HD mice. PGC-1α expression is regulated directly by the CREB–TAF4 complex, which is impaired by mutant huntingtin, abolishing its ability to bind to the PGC-1α promoter [145]. An alternative possibility is that mutated huntingtin binds directly to PGC-1α, affecting its ability to up-regulate expression of its downstream targets [145,146].

ELEVATED ROS (REACTIVE OXYGEN SPECIES) AND MITOCHONDRIAL DYSFUNCTION IN HD

ROS and metabolic mitochondrial dysfunction have been implicated in many neurodegenerative diseases [147149]. Mitochondria are the major source of ROS production [150] and, at the same time, are also a key target for ROS damage. The respiratory chain (especially complex I and the Q cycle operating in complex III) generates superoxide, which is converted into hydrogen peroxide by MnSOD (manganese superoxide dismutase) [151,152]. Hydrogen peroxide can react with the available iron to produce the extremely reactive hydroxyl radical [153]. Superoxide also reacts with nitric oxide to produce the dangerous peroxynitrite [154], which inhibits the respiratory chain [155] and inactivates aconitase and MnSOD [156,157]. Superoxide can also directly inactivate certain Fe–S proteins such as aconitase [158,159]. To protect the cell against ROS damage, mitochondria contain a variety of antioxidant systems. These include non-enzymatic components, such as α-tocopherol, coenzyme Q10 or glutathione, as well as enzymatic components such as MnSOD, catalase and glutathione peroxidase [160,161]. However, excessive production of ROS or a disruption of the antioxidant mechanisms can lead to oxidative damage to mitochondrial protein, lipid and DNA [162].

Evidence from post-mortem brains of HD patients and transgenic mouse models suggests that mitochondrial metabolic dysfunction could play a role in HD pathogenesis [163165]. Mitochondrial impairment and oxidative stress have even been detected in asymptomatic HD carriers [166], indicating that this may be an early step in disease development. It is, however, not clear whether metabolic mitochondrial dysfunction is a primary cause in HD or a secondary consequence underlying neuronal loss [167]. One possible mechanism of how mutant huntingtin could lead to mitochondrial impairment is through direct association with the outer mitochondrial membrane, which was shown in brain mitochondria from transgenic mice expressing a pathological CAG-repeat and isolated mitochondria from lymphoblasts of HD patients [168171].

In addition to energy production and metabolism, mitochondria also play an important role in cellular calcium homoeostasis and apoptosis [172,173], and isolated mitochondria from HD mice also showed decreased membrane potential, depolarized at lower calcium loads compared with controls [170] and were more sensitive to calcium-induced cytochrome c release [168]. These effects could be reproduced by incubating normal mitochondria with mutant huntingtin in vitro.

A relationship between the number of CAG repeats and mitochondrial ATP production has been reported [174]. In huntingtin striatal cells, the ATP/ADP production decreases as repeat numbers increase, whether in the normal or the disease-causing range. The decreased ATP/ADP ratio was linked to enhanced calcium influx through NMDA receptors. Impaired energy metabolism probably leads to reduced ATP production, with a concomitant reduced mitochondrial membrane potential and a higher vulnerability to NMDA-mediated calcium influx and excitotoxicity [175,176]. Calcium influx could trigger further free radical production, exacerbating cell damage. There is also a potentiating effect of mutant huntingtin on NMDA receptor activity as NMDA-evoked currents and NMDA-mediated calcium transients were significantly increased in striatal neurons from YAC72 transgenic mice compared with wild-type controls, which could lead to an increased vulnerability to excitotoxicity [177,178]. Also, calcium influx through the NMDA receptor results in impaired mitochondrial function and increased oxidative stress [179,180].

Brain mitochondria have a higher concentration of lipids with polyunsaturated acyls, which are more sensitive to oxidative damage than other lipids [181]. An increase in striatal lipid peroxidation was observed in HD transgenic mice which paralleled the worsening of the neurological phenotype [182]. The overall effects of lipid peroxidation probably decrease membrane fluidity, making it easier for phospholipids to exchange between the two halves of the bilayer. This would increase the leakiness of the membrane to substances that do not normally cross it other than through specific channels, and also cause damage and inactivation of membrane proteins, receptors, enzymes and ion channels [183]. Products of the lipid peroxidation process, such as 4-hydroxyhexenal and 4-hydroxynonenal, have also been shown to facilitate the induction of mitochondrial permeability transition [184], which could lead to cell death by release of apoptogenic factors.

Mutant huntingtin has been shown to directly impair the motility of mitochondria, with aggregates probably acting as ‘physical roadblocks’ for mitochondrial transport [81,185]. Aggregates may impair the passage of mitochondria along neuronal processes, causing them to accumulate adjacent to aggregates and become immobilized [185]. This may heighten glutamate excitotoxicity and alter calcium handling owing to the inability to transverse the neurite.

ROS can cause direct damage to DNA, and an enhanced ROS production may lead to accumulation of somatic mutations [186]. 8-OHdG (8-hydroxy-2′-deoxyguanosine) is a biomarker for oxidative DNA damage and increased levels of this ROS-damaged guanine nucleotide were found in mtDNA (mitochondrial DNA) from HD post-mortem parietal cortex [187] as well as in R6/2 HD transgenic mice [188]. Also, increased oxidative damage to total DNA was found in caudate and frontal cortex of HD post-mortem brain [189]. 8-OHdG can cause nucleotide base mispairing, resulting in DNA point mutations, probably leading to respiratory dysfunction, higher rates of ROS production and higher susceptibility to apoptotic stimuli [190192].

In addition to showing meiotic instability, the HD mutation also shows somatic instability. Different CAG repeat lengths are seen in different neurons. Whether or not this has an impact on disease severity is not certain, but this phenomenon is certainly an attractive contributor to pathology. A recent study showed that the age-dependent CAG somatic mutation events associated with HD occur in the process of removing oxidized base lesions, and are largely mediated by the single base excision repair enzyme, OGG1 (7,8-dihydro-8-oxoguanine-DNA glycosylase) [193]. OGG1 is activated in response to oxidative DNA lesions and results in somatic instability. This initiates a potential positive-feedback loop, since longer CAG stretches will lead to even more oxidative damage and hence more OGG1 activity [193].

ROS may also result in the formation of protein carbonyls; oxidatively modified proteins and enhanced protein carbonyl levels have been found in the striatum of R6/2 mice [194196]. These modified proteins are generally dysfunctional owing to loss of catalytic or structural integrity, which may lead to decreased activities of key metabolic enzymes and disturbed cellular signalling systems [195,197,198].

It is interesting to consider that many of the pathogenic process proposed in HD pathogenesis may interact, and this potential cross-talk may lead to various types of positive-feedback loops (see Figure 2 for examples).

EVIDENCE FOR AND AGAINST THE IMPAIRMENT OF THE UPS (UBIQUITIN–PROTEASOME SYSTEM) IN HD

It has been proposed that the UPS is impaired in HD and that this contributes to the disease mechanism. However, this is controversial, and conflicting results have been obtained from different assays performed in a variety of different HD model systems. Some groups have demonstrated decreased proteasome activity [199,200], some have shown no change in activity [201,202] and others have even demonstrated an increase in proteasome activity [203,204] in response to mutant huntingtin expression.

The UPS consists of multiple components and is not only important for protein turnover, but also essential for normal cellular and physiological function [205,206]. At the centre of the UPS is the 20S catalytic core of the proteasome. This is a barrel-shaped multisubunit complex that has three main proteolytic activities: chymotrypsin, trypsin and peptidyl-glutamyl that cleave after hydrophobic, basic and acidic residues respectively [207]. 19S regulatory particles (also termed PA700) bind either side of the 20S core proteasome to form the 26S proteasome [208]. A cascade of enzymes act to covalently attach multiple ubiquitin molecules to target proteins, which mark them for degradation [209]. Polyubiquitin chains are recognized by the 19S regulatory particle, which facilitates protein degradation by ATP-dependent de-ubiquitination and unfolding of the target protein, and opening the outer rings of the 20S core proteasome. The activity of the proteasome can be altered by its association with a number of regulatory molecules and complexes such as the PA28 family of proteasome activators, which enhance the degradation of short peptides [210] and Rad23, which is thought to shuttle ubiquitinated proteins to the proteasome [211]. In addition, the catalytic activity of the proteasome can also be modulated by alterations in subunit composition in response to cellular stimuli [e.g. IFNγ (interferon γ) induction of immunoproteasome subunits LMP (low-molecular-mass polypeptide) 2 and LMP7 to bias proteolysis in favour of producing short peptides suitable for MHC-1 presentation at the cell surface] [212].

Although responsible for the degradation of short-lived and damaged proteins, the UPS indirectly regulates other cellular activities. The UPS also has a role in cell signalling through the degradation of many key regulatory proteins, protein subunits and transcription factors such as p53 and IκB (inhibitor of nuclear factor κB). Recently, it has been proposed that the proteasome has a role in normal synaptic function and plasticity, and is involved in the NMDA-dependent remodelling of the protein composition of synapses [213]. Thus impairment of the UPS is likely to have a detrimental effect on the function of the cell and indeed the whole organism.

The idea that the UPS may be impaired in polyglutamine expansion disorders initially came from studies showing the labelling of polyglutamine aggregates with antibodies raised against ubiquitin and proteasome subunits in cell models [100,214], transgenic mice [87] and human post-mortem samples [95]. From these observations, the sequestration hypothesis was proposed. It suggested that the sequestration of UPS components in aggregates and the altered subcellular localization of proteasomes might affect UPS activity. However, in contrast with the sequestration hypothesis, inhibition of the proteasome has been demonstrated in cells co-expressing a GFP (green fluorescent protein)–degron (GFP tagged to ubiquitin) construct and pathogenic Htt exon 1 constructs in the absence of visible aggregates [215], and there is some evidence to suggest that some molecules are not sequestered tightly into aggregates, but are only loosely associated and can diffuse freely [216]. Another model to account for the impairment of the proteasome in HD came from both in vitro and cell model data suggesting that expanded polyglutamine-containing proteins are not easily degraded by the eukaryotic proteasome, which can only accommodate unfolded proteins [217,218]. As these studies show that the proteasome cannot cleave between successive glutamine residues in a polyglutamine tract, the choking hypothesis proposes that proteins containing expanded polyglutamine tracts may get ‘stuck’ in the proteasome and block the entry of other substrates into the barrel of the 20S catalytic core. Although it has been shown that synthetically generated polyglutamine aggregates do not inhibit 26S proteasome function in vitro [215], it has recently been shown that fibrillar species purified from HD transgenic mouse and human HD post-mortem brains do decrease proteasome activity in vitro [219].

The first study to measure proteasome activity in HD cell models directly used a fluorigenic substrate specific for the chymotrypsin activity of the proteasome [200]. A shift in chymotryspin activity was demonstrated from cytosolic fractions to aggregate-containing precipitated fractions derived from lysates from both a stable HD cell model (expressing huntingtin exon 1 with a 150 polyglutamine repeat) and brain lysates derived from R6/1 mice [200]. Chymotrypsin activity was reduced in the cytosolic fraction and increased in precipitated fractions derived from lysates of polyglutamine-expressing cells compared with control cells [200]. This suggested the altered localization of proteasomes to aggregates. The authors also demonstrated reduced degradation of the endogenous proteasome substrate, p53 [200]. This study strongly suggested the impairment of the UPS in HD. Subsequently, these data were supported further by a study in cells using a reporter molecule comprising EGFP (enhanced GFP) fused to a short sequence that targets the protein for proteasome degradation (termed degrons) [199]. When this EGFP–degron reporter was co-expressed with mutant huntingtin in cells, EGFP fluorescence was increased more than 2-fold compared with cells expressing wild-type huntingtin. This observation implicates a major impairment of the proteasome function because >50% decrease of chymotrypsin-like activity is required to obtain a 50% increase of GFP fluorescence [199]. Similar results were found with the ΔF508 mutant cystic fibrosis membrane conductance regulator, an unrelated protein sharing only the propensity to aggregate, suggesting that proteasome impairment is caused by aggregate formation [199]. Consistent with these data, a reduction of chymotrypsin and peptidyl-glutamyl activities has been demonstrated in lysates from human HD post-mortem brains and HD patient skin fibroblasts [220].

Using the co-expression of NLS- or NES-tagged EGFP–degrons and NES or NLS mutant polyglutamine constructs, a global impairment of the UPS was demonstrated, regardless of the intracellular locations of the proteins containing the expanded polyglutamine tracts or the degron reporters [215]. The authors also examined two hypotheses proposing mechanisms for the inhibition of proteasome activity. Contrary to the sequestration hypothesis being the only mechanism, they demonstrated proteasome inhibition in the absence of visible aggregates. They also showed that synthetic protein aggregates do not inhibit activity of the 26S proteasome function in vitro, suggesting that UPS impairment is unlikely to be caused solely by blocking the proteasome. Indeed, the decreases in nuclear proteasome function by extranuclear mutant polyglutamine and vice versa, argued that the observed effects were independent of interactions between mutant protein and the proteasome. Nevertheless, one cannot discount either of these models, as fibrillar forms of huntingtin purified from transgenic mouse and human post-mortem brains do inhibit the 26S proteasome in vitro [219]. Furthermore, an accumulation of proteasome substrates may occur in the presence of normal proteasome function, owing to abnormalities in ubiquitination, de-ubiquitination or compromise of the activities of various shuttling proteins that may be required to traffic ubiquitinated proteins to the proteasome.

Data contrary to the above, suggesting that the proteasome is not impaired in polyglutamine expansion disorders, come from a variety of sources. SH-SY5Y cells stably expressing mutant huntingtin did not show a difference in the degradation of fluorigenic peptides, compared with cells expressing wild-type huntingtin [201]. Also, an increase (not decrease, as expected) in the chymotrypsin and trypsin activities of the proteasome was observed in lysates derived from the cortex and striatum of the HD94 conditional mouse model of HD [203]. This was attributed to an increase in the levels of the proteasome subunits LMP2 and LMP7 and the induction of the immunoproteasome. Increased proteasomal chymotrypsin-like activity has also been observed in brain lysates from the R6/2 model of HD compared with non-transgenic littermates [204]. However, this study found no change in overall 26S proteasome activity and showed that the nuclear proteasome activator PA28 (also termed REGγ) is not involved in polyglutamine pathology [204]. This is in contrast with data demonstrating the reversal of proteasome dysfunction in mutant-huntingtin-expressing striatal neurons and rescue of cell death by PA28 overexpression [221].

One of the caveats of studies in cell culture and many transgenic models is that they express artificially high levels of mutant proteins, which may induce proteasome dysfunction either directly or indirectly. The role of the proteasome in vivo has recently been tested using the knockin mouse model of SCA7 (a polyglutamine expansion disorder caused by mutations in ataxin 7) crossed with a transgenic mouse expressing an EGFP–degron reporter [202]. The authors observed an increase in levels of the reporter in neurons at late stages of the disease. However, this was not due to inhibition of proteasome activity, but instead correlated with an increase in mRNA coding the EGFP–degron reporter [202].

Thus it still remains unclear whether the UPS is impaired in HD. Conflicting data are likely to occur as many of the experimental approaches used to assess UPS function have caveats. For instance, studies of UPS function have been performed in many different models of HD (stable, inducible and transient cell models, transgenic Drosophila, transgenic mice and human post-mortem samples). These models may represent different stages of the human disease and express HTT transgenes of different sizes (e.g. full-length huntingtin or smaller exon 1 fragments) at different levels under the control of different promoters. In addition, the various reporters used are likely to be assessing the activity of different components of the UPS. One problem with assays of isolated proteasome activity using small fluorigenic peptides is that modest changes in proteasome number/activity may not be rate-limiting for substrate clearance. It is likely that ubiquitin conjugation, and, in some situations, transport of ubiquitinated proteins to the proteasome, may be more important physiological regulators, and these will not be measured using these substrates. This has been partially circumvented by using EGFP–degron reporters and measuring levels of endogenous UPS substrates such as p53. However, levels of artificial EGFP–degron reporters may be affected by changes in mRNA encoding the reporter [202]. Likewise, protein levels of endogenous proteasome substrates such as p53 are likely to be affected not only by UPS activity, but also by changes in transcription elicited by mutant huntingtin [26]. In order to try to overcome these problems, UPS function has recently been assessed using polyubiquitin chains as an endogenous biomarker [222]. The amount of polyubiquitin chains within a cell was shown be a faithful indicator of UPS function and, using this approach, impairment of the UPS was demonstrated in brain lysates from R6/2 HD transgenic mice, the HdhQ150/Q150 knockin model of HD and human HD post-mortem brains [222]. One question raised by this study is whether the increased numbers of ubiquitin chains are necessarily due to proteasome dysfunction, or an increase in the ubiquitination rate of substrates. In other words, although the amounts of polyubiquitin chains will increase when proteasome function is disrupted, they can also increase in the context of normal proteasome activity or under conditions where substrate degradation is enhanced (for instance, if induction of ubiquitination exceeds substrate clearance). Thus, although this study is consistent with data suggesting impaired proteasome function in HD, it is still not definitive, and the conflicting results of previous studies must be properly resolved before it is proposed that the UPS is truly impaired in HD.

THE UPS AND DEGRADATION OF MUTANT HUNTINGTIN

One strategy for the treatment of polyglutamine expansion disorders is to decrease levels of the toxic mutant protein. This could be achieved by increasing the clearance of the mutant protein. Indeed, induction of autophagy by treatment with the mTOR (mammalian target of rapamycin) inhibitor rapamycin has been demonstrated to reduce aggregation and attenuate toxicity in HD cell and mouse models [223].

It is unclear whether proteins with an expanded polyglutamine tract are good proteasome substrates. Huntingtin interacts with the human ubiquitin-conjugating enzyme E2-25K, which requires the polyglutamine domain [55]. Parkin, an E3-ubiquitin ligase, also co-localizes with mutant huntingtin aggregates in HD mouse and human brains, and overexpression of parkin enhances the clearance of the mutant protein [224]. These data suggest that huntingtin may be a proteasome substrate. Consistent with this, proteasome inhibitors such as lactacystin and epoxomycin prevent mutant huntingtin clearance in a conditional HD mouse or cell models after its expression is stopped [225]. Proteasome inhibition also increases mutant huntingtin aggregation and toxicity in HD cell models [100,200,225227]. As the proteasome is unable to cleave between glutamine residues within polyglutamine tracts [217,218], up-regulation of proteasome activity would possibly reduce the levels of proteins with polyglutamine expansions and associated flanking sequences, producing increased levels of long isolated polyglutamine tracts. Such products are predicted to be more toxic than the inputs that have flanking sequences. However, such products have been shown to be degraded by puromycin-sensitive aminopeptidase, albeit very slowly and inefficiently [228]. It is unclear whether the substrate capacity of puromycinsensitive aminopeptidase could be overwhelmed if proteasome activity were increased. In addition, modulation of the proteasome may not be a good therapeutic strategy. The proteasome has a key regulatory role, and altering its rate of degradation may have many side effects. One may be able to use chemical chaperones such as trehalose or Congo Red to increase the degradation of polyglutamine-containing proteins, as these agents shift the equilibrium towards increasing the levels of soluble monomeric proteasome-accessible species and away from aggregates [229,230]. This may make the polyglutamine proteins more accessible to the proteasome.

NON-CELL-AUTONOMOUS PROCESSES IN HD

Much of the focus on pathogenic mechanisms in HD has focused on cell-autonomous mechanisms. Although less attention has been focused on the pathological role of huntingtin in cell–cell interactions, a number of studies suggest that non-cell-autonomous mechanisms may also contribute to disease pathogenesis.

MSNs (medium spiny neurons), which are particularly vulnerable to the HD mutation, are innervated by glutamatergic axons, and overstimulation of glutamate receptors can induce cell death via excitotoxicity [231]. HD transgenic mouse models show increased NMDA receptor activity in neurons [178,232]. The abundant glutamatergic afferents to MSNs and the NMDA receptor subunit composition in MSNs [233,234] may contribute to their preferential vulnerability in HD, especially when the glutamatergic input is increased or the clearance of extracellular glutamate is decreased. Clearance of extracellular excitatory neurotransmitters is largely performed by glutamate transporters [GLT-1 (glutamate transporter-1) and GLAST (glutamate aspartate transporter)] in astrocytes, the major subtype of glia [235]. Huntingtin can reduce the expression level of GLT-1 in the brains of HD transgenic mice and Drosophila [236,237]. A decreased activity of GLT-1-dependent glutamate uptake in astrocytes leads to an increase of glutamate concentration extracellularly. This may then lead to increased and deleterious calcium entry in striatal neurons. All of these events may contribute to the activation of ATP- and calcium-dependent deleterious enzymes such as calpains, caspases and endonucleases [238].

Elegant glial–neuron co-culture experiments showed that N-terminal huntingtin in glia promoted the death of cultured neurons that did not express huntingtin [239]. Huntingtin may affect various functions of glial cells, including their production of chemokines and neurotrophic factors. The neurodegeneration caused by overexpressed N-terminal huntingtin in neurons in vitro is reduced in the presence of glial cells. The conclusion might be that glial dysfunction contributes more to pathology than glial degeneration itself.

Another type of non-cell autonomous mechanism in HD comes from studies in mouse models expressing toxic mutant huntingtin fragments either in all neurons in the brain or only in cortical pyramidal neurons, which are vulnerable in HD [240]. Restriction of huntingtin expression to cortical pyramidal neurons was sufficient to produce nuclear accumulation, but insufficient to produce neuropathology or motor deficits. However, expression in all of the neurons showed both progressive motor deficits and HD cortical pathology via nuclear accumulation, aggregation, reactive gliosis, dysmorphic neurites and dark neuron degeneration. One attractive possibility is that mutant huntingtin in cortical interneurons attenuates the ability of these neurons to mediate inhibition on their target pyramidal neurons and that this loss of inhibition contributes to pathology. However, these data do not preclude a combination of cell-autonomous and non-cell-autonomous mechanisms working in concert.

GENETIC SCREENS REVEAL MANY NOVEL PATHWAYS IN HD PATHOGENESIS

HD pathology may be a result of the cumulative effect of a variety of pathway perturbations. Many candidate-based approaches for HD treatment have identified target pathways, but searches for novel modifiers of HD pathology may allow us to identify further targets for therapeutic intervention as well as gain a better understanding of the pathology. One way of identifying such targets is through genetic or chemical screens.

Yeast two-hybrid screens have been used extensively for identifying huntingtin interactors [55,241247]. Hap1, Hip2, Hip1 and CBS (cystathionine β-synthase), as well as many other proteins, have been identified as mutant huntingtin protein interactors. A study based on a vast network of 186 protein–protein interactions [248], identified GIT1 [GPCR (G-protein-coupled receptor) kinase-interacting protein 1], as a novel interactor. Interestingly, GIT1 associates with wild-type huntingtin in mammalian cells, but, in pathogenic circumstances, GIT1 localizes to mutant huntingtin aggregates and is required for their formation. In HD brains, GIT1 is cleaved, resulting in altered function.

Recently, Kaltenbach et al. [249] performed a yeast two-hybrid screen, as well as affinity pull-downs with MS, to identify huntingtin interactors. Out of 234 novel protein targets identified, an arbitrary set of 60 genes encoding interacting proteins were tested for their ability to behave as genetic modifiers of neurodegeneration in a Drosophila model of HD. This high-content validation assay showed that 27 of 60 orthologues tested were high-confidence genetic modifiers involved in a variety of pathways such as synaptic transmission, signal transduction, transcription and cytoskeletal organization. This study provides powerful evidence that huntingtin interactors are a particularly enriched source of HD modifiers.

Many screens have attempted to identify genetic and pharmacological modifiers of aggregate formation and clearance. A cell-free filter retardation assay identified benzothiazole derivatives as inhibitors of the formation of HD-insoluble aggregates [250], whereas a cell-based screen identified a lead compound that was able to specifically clear mutant huntingtin protein, but not normal huntingtin [251]. Yamamoto et al. [252] used a gene array in a cell line that established transcriptional changes induced by the mutant huntingtin protein. Genes that were up-regulated were targeted using siRNA (short interfering RNA) molecules to decrease expression. Of these up-regulated genes, 23 were required for clearance of the mutant huntingtin protein. Activation of IRS-2 (insulin receptor substrate 2), which is involved in signalling from insulin and IGF-1 (insulin-like growth factor 1), enhanced the clearance of aggregate-prone proteins.

A genome-wide RNAi (RNA interference) screen has been used to identify loss-of-function enhancers of aggregation in a Caenorhabditis elegans model of polyglutamine disease [253]. The 186 genes that enhanced aggregation were involved in a variety of pathways, such as RNA metabolism, protein synthesis, protein folding, protein degradation and protein trafficking, reflecting a diversity of potential cellular pathways that may have an impact on polyglutamine disease pathogenesis.

A number of cell-based assays have aimed to identify modulators of polyglutamine toxicity [254,255]. A screen of 4850 haploid mutants in a yeast (Saccharomyces cerevisiae) model identified 52 enhancers and 28 suppressors of mutant Htt exon 1-Q53-induced toxicity [256,257]. The enhancers are involved in cellular processes such as protein folding, response to stress and the UPS [257]. Suppressors of toxicity are involved in transcription, protein aggregation, vesicle transport, vacuolar degradation and the kynurenine pathway, which is involved in tryptophan degradation [256]. These studies suggest that yeast models may provide important insights into the biology of HD.

Rescue of cellular toxicity has also been studied in the nematode worm. A C. elegans model expressing N-terminal huntingtin carrying a stretch of 150 glutamine residues in the glutamatergic ASH sensory neurons leads to their degeneration by day 8 [258]. In a genetic screen, for the enhancement of neurodegeneration, loss of pqe-1 (polyglutamine enhancer 1) gene function enhances neurodegeneration and pqe-1 overexpression rescues cellular toxicity. This gene encodes a putative glutamine-rich RNA exonuclease, which may rescue toxicity by sequestrating polyglutamine-expanded proteins.

Drosophila models of neurodegenerative diseases have recently been established and genetic screens in Drosophila have provided a number of modifiers. These include hsp40-like J domains proteins (dHDJ1 and dTPR2) [259]. Molecular chaperones have been implicated in the rescue of other polyglutamine-induced pathogeneses in Drosophila, as well as in other models [260262]. A novel modifier has been identified, dMLF1, the Drosophila homologue of human MLF1 (myeloid leukaemia factor 1), which suppresses toxicity by potentially inhibiting mutant polyglutamine protein aggregation [263]. A SCA1 Drosophila model expressing ataxin-1(82Q) under the gmr driver, leads to severe external eye abnormality and reduced retinal thickness [264]. Genetic screens with this model identified genes involved in protein-folding/heat-shock response, cellular detoxification, nuclear transport, RNA processing and transcriptional cofactors as modifiers of polyglutamine pathogenesis. Recently, a screen of a Drosophila model of SCA3 identified the miRNA bantam a suppressor of toxicity [265], revealing a further possible modifier pathway.

THERAPY FOR HD

HD has a number of features which make it a comparatively tractable problem, compared with neurodegenerative diseases which do not have Mendelian inheritance. Its autosomal dominant nature and single type of mutation allows most people at risk to be potentially identified before symptoms develop, making pre-symptomatic treatment a feasible possibility. This is important because a significant amount of neuronal loss has already occurred by the time most neurodegenerative diseases present clinically, lowering the rate of loss is potentially easier than repairing damage after it has occurred. The development of therapeutic strategies for HD may have wider relevance, most obviously for the eight other polyglutamine diseases, but even possibly for other neurodegenerative conditions characterized by abnormalities of protein conformation.

There are no disease-modifying treatments for HD in routine clinical use, and current treatment is therefore symptomatic. Although many trials have concentrated on mechanisms and outcomes associated with movement disorder, patients report that their quality of life is more often decreased by psychiatric manifestations of their condition, including depression, irritability and apathy [266]. Rates of depression may be as high as 40%, and suicide may occur in as many as 10% [267,268]. Obsessive compulsive symptoms are also common [269]. Given their frequency and impact, it is surprising that the evidence base for treatment of psychiatric disturbance is limited to case studies. SSRIs [selective serotonin (5-hydroxytryptamine)-re-uptake inhibitor] or mirtazapine may be preferred for depression as they have a more favourable anticholinergic profile compared with some other antidepressants [270]. Improvement in depression and obsessional thinking has also been reported with olanzapine and sertraline [271,272]. Risperidone and amisulpiride may have a role in the treatment of psychosis in HD [273,274], while there are reports of quetiapine helping with behavioural disturbance [275].

A major neurological symptom associated with HD is chorea. Tetrabenazine depletes dopamine from central neurons. The first relatively large randomized control trial of its use in HD [276] found that tetrabenazine did significantly improve the UHDRS (unified HD rating scale) and global improvement assessments, but was associated with an increased incidence of adverse effects, including one suicide. Atypical antipsychotics are often used in the clinic, although the evidence from a larger trial of clozapine showed disappointing efficacy with significant side effects [277]. More encouraging results are reported for olanzapine, but from small open-label studies [278]. Strikingly, there are limited data providing conclusive support for any cognitive-enhancing therapies in HD. A study in a small number of HD patients treated with rivastigmine suggested possible motor and cognitive benefit [279]. These results were not supported by a further small trial of donepezil [280]. Given the limited proven efficacy of symptomatic treatments, an important part of treatment is co-ordinating appropriate social, paramedical and palliative care for HD patients.

Although further work towards developing and validating symptomatic treatments is clearly justified, the steadily increasing knowledge base around potential pathways leading to neurodegeneration in HD provides the possibility to develop rational mechanism-based therapies that may slow the neurodegeneration and neurological dysfunction at the core of this disease. We have selected a few possible examples of such therapeutic strategies that have been initiated largely in cell and animal models, before conducting studies in humans (Figure 3).

Potential disease-modifying strategies for HD

Figure 3
Potential disease-modifying strategies for HD

HD toxicity may be ameliorated by direct modification of the mutant gene or protein. Strategies which seek to achieve this include repression of mutant gene expression, inhibition of aggregation or misfolding, inhibition of the cleavage of the protein to form toxic fragments and increased clearance of the mutant protein by up-regulating autophagy. Alternative strategies depend on mitigating the deleterious effects of the mutant protein by stabilizing mitochondria or correcting transcriptional dysregulation. More general neuroprotective strategies which may be important include attempts to decrease excitotoxic cell death or enhance neurotrophin release. See the text for more details.

Figure 3
Potential disease-modifying strategies for HD

HD toxicity may be ameliorated by direct modification of the mutant gene or protein. Strategies which seek to achieve this include repression of mutant gene expression, inhibition of aggregation or misfolding, inhibition of the cleavage of the protein to form toxic fragments and increased clearance of the mutant protein by up-regulating autophagy. Alternative strategies depend on mitigating the deleterious effects of the mutant protein by stabilizing mitochondria or correcting transcriptional dysregulation. More general neuroprotective strategies which may be important include attempts to decrease excitotoxic cell death or enhance neurotrophin release. See the text for more details.

Preventing mutant gene expression is an attractive strategy, as it aims to remove the primary culprit: the toxic mutant protein. Human individuals with only one working copy of the HTT gene suffer no obvious adverse consequences. It has been possible to use siRNA in mouse models of HD [281] and other polyglutamine diseases [282] to decrease mutant protein expression and aggregation and prolong survival. These trials used direct intraventricular injection of the siRNA, a technique that may be relatively less acceptable to human sufferers. There are safety issues that will need to be addressed for this therapeutic approach. First, the knockdown must be specific to the mutant form of the protein and the wild-type should ideally be unaffected (as it may have anti-apoptotic functions). Although it may be possible to target the mutant allele to some extent using single nucleotide polymorphisms, these are likely to show interindividual variation and therefore require a library of siRNAs [283]. Other safety concerns centre on both off-target effects (decreasing expression of genes other than the HTT gene) and inactivation of tumour-suppressor genes. These current technical difficulties and safety concerns mean that, although these techniques are potentially exciting, their use in clinical trials may be somewhat more distant.

If it is not possible to silence production of the mutant protein, then enhancing its clearance may be an alternative (or adjunct). Mutant huntingtin is cleared by autophagy, a process involving the formation of double-membrane structures called autophagosomes around a portion of cytoplasm. These autophagosomes ultimately fuse with lysosomes, where their contents are degraded. The strategy of up-regulating autophagy to increase clearance of mutant protein has shown promise in cell, Drosophila and mouse models of HD where the increase in clearance shows a preference for the mutant form of the protein [223]. Drugs which can be used to up-regulate autophagy (rapamycin, carbamazepine, sodium valproate) are already U.S. FDA (Food and Drug Administration)-approved and some have a long track record in treating human CNS (central nervous system) disease. This approach is also one where the principle has been shown to work in animal and cell models expressing other aggregate-prone proteins that lead to human disease, including tau and mutant α-synuclein [284].

Ideally, we would like to develop drugs that target putative pathological mechanisms. One process that may be rate-limiting is huntingtin cleavage by caspases and other proteolytic enzymes. Indeed, the importance of cleavage of huntingtin and the role of apoptosis in HD have been described above. Inhibitors of the enzymes which cleave mutant huntingtin to its toxic N-terminal fragment(s) (including caspases 2, 3 and 6 and calpain) may provide potential targets for therapeutic intervention. Given the role of caspases in induction of apoptosis their inhibition may be doubly attractive. Broad-spectrum caspase inhibitors increased survival in an exon 1 mouse model, but required intracerebral administration [285]. However, there may be cancer risks with long-term caspase inhibition. Minocycline may prevent apoptosis by inhibiting the mitochondrial permeability transition and is a caspase inhibitor (although it probably has a range of properties). Despite mixed results in mouse models [286,287], its history of long-term use in humans as an antibiotic has encouraged human trials. A small trial in humans has suggested benefit [288] and good tolerability has been reported in larger trials, the final outcome of which is awaited [289].

The potential importance of mitochondrial dysfunction and its implication in cell death in HD has already been described. Compounds which enhance mitochondrial stability have been investigated. Improvements in survival, neuropathology and motor performance have been reported in mouse models treated with creatine [290], and early results from its use in human sufferers suggest good tolerability [291].

Other potential treatments that have been investigated include transglutaminase inhibitors. Transglutaminases belong to a family of closely related proteins that catalyse the cross-linking of a glutamine residue of a protein/peptide substrate to a lysine residue of a protein/peptide co-substrate with the formation of a GGEL [Nϵ-(γ-L-glutamyl)-L-lysine] cross-link. These bonds may be important in the formation of aggregates and the toxicity of mutant huntingtin. Cystamine is a transglutaminase inhibitor which improves survival, motor phenotype and neuropathology in mouse models [292], and preliminary dose-finding and tolerability trials in human sufferers have been completed [293].

Chaperones help proteins to adopt more stable conformations and prevent aggregation, and their production is increased in heat-shock responses. Chaperones may be induced by chemical initiators of heat-shock responses such as geldanamycin which is protective in cell models of HD [294]. Small-molecule ‘chemical chaperones’ such as trehalose have a similar effect and have shown beneficial effects in mouse models of HD [295].

Mutant huntingtin binds a number of transcription factors, of which the best described is CBP [125]. CBP acetylates histones and thereby exposes the DNA sequence to allow transcription. Given that the mutant huntingtin therefore results in decreased histone acetylation, HDAC inhibitors have been investigated as a therapeutic strategy. These drugs have shown efficacy in both Drosophila [127] and mouse models [130] and one (phenylbutyrate) has long-term safety data in humans in the treatment of ornithine transcarbamylase deficiency [296]. However, current HDAC inhibitors have major side effects.

Excitotoxic cell death in HD is implicated by the reproduction of HD pathology by NMDA agonists and the increased sensitivity of NMDA receptors in the presence of mitochondrial dysfunction. As a result, there has been interest in NMDA receptor antagonists as a potential therapeutic strategy. Murine models show increased survival with the NMDA receptor antagonists riluzole [297] and remacemide (alone and an additive effect with coenzyme Q10) [298]. Amantadine, riluzole, lamotragine and remacemide have all been studied in human randomized controlled trials. The results for both amantadine and riluzole have been mixed, although, in both cases, the results from the largest and best-designed trials have been disappointing [299,300]. A relatively large (n=55) double-blind randomized control trial of lamotragine for 30 months found no significant difference in primary or secondary response variables [301]. In one of the largest trials in HD to date, 347 patients were randomized to either coenzyme Q10 or remacemide, both or neither for 30 months. Sadly, the encouraging results from the mouse study were not replicated, with no treatment arm showing advantage over placebo [302]. Memantine (an NMDA antagonist licensed in the U.K. for Alzheimer's disease) has shown some promise in an open-label trial, but this remains to be confirmed using more rigorous methodology [222]. It should be noted that many of the compounds described act via more than one mechanism. For example, creatine is a transglutaminase inhibitor as well as having mitochondrial effects, and coenzyme Q10 may have effects on mitochondrial stability and amelioration of excitotoxicity as well as being an antioxidant.

One way to repair neuronal loss in HD may be with transplantation. Studies in HD mouse models transplanting either fetal striatal grafts [303] or wild-type cortex [304] showed the potential for graft survival and some modest improvements in phenotype. Trials have been carried out in humans, mostly using tissue from human fetuses [305309], although one used porcine material [310]. Results from these trials have been encouraging in terms of graft survival and largely also in terms of safety (although, in one study, of the seven patients transplanted, three developed subdural haematomas [311]). Although graft survival and function has been promising using proxy measures of glucose uptake [312] and post-mortem examination [313], the symptomatic benefits have been less clear-cut (although the trials have been largely associated with stability or slowed decline of motor symptoms). Although this approach may have potential, there is still much to do in terms of determining the optimal source and storage method of graft tissue (including the possibility of stem cell sources), choice of recipient, location of graft, graft susceptibility to disease process, rating of outcome, use of immunosuppression and study design (including the possible use of sham surgery to provide control). The results of longer-term follow-up trials currently underway are awaited. Also, grafting striatum may have potential value in alleviating motor symptoms, but is unlikely to be able to have a significant impact on the cognitive features of this disease which are likely to be due to the extensive cortical damage.

Neuronal loss in HD results in decreased availability of neurotrophic factors to adjacent neurons and subsequently further neuronal loss. The relationship between growth factors and mutant huntingtin appears to be antagonistic, with each being down-regulated by the presence of the other [35,314]. Difficulties crossing the blood–brain barrier and side effects associated with parenteral administration have resulted in trials of centrally administered neurotrophic factors. Cells engineered to express neurotrophins can be encased in capsules which protect them from host immune defences, but allow the release of neurotrophins. This approach has been used successfully in primate toxin models [315] (which may bear only distant resemblance to human HD) and Phase I trials have been conducted in humans [316]. Safety results from this trial were reassuring, and, although the clinical benefits were not significant, the results were encouraging and further data are awaited.

In the 14 years since the causative gene in HD was discovered, huge advances have been made in understanding the biology of the disease and in designing rational therapeutic strategies which work well in animal models. Despite this, there remains no disease-modifying treatment. The challenge for the next decade will be translating laboratory data into clinical treatments, but, given the progress of the past, it is a challenge which can be viewed with optimism. Furthermore, it remains a challenge to conduct clinical trials in human HD, given its insidious onset and slow multifaceted progression. A further challenge will be to learn how to conduct powerful and cost-efficient trials to explore the growing repertoire of strategies emerging from more basic research studies. These may be considerably simplified by the identification of suitable biomarkers for disease progression [317].

We thank Michael Jardine and James Tweedley for help with illustrations. Work in D. C. R.'s laboratory on HD is funded by the MRC (Medial Research Council), the Wellcome Trust (Senior Fellowship to D. C. R.), Action Medical Research (Research Training Fellowship to B. R. U.), Sackler scholarship (B. R. U.), EU (European Union) [EUROSCA (European Integrated Project on Spinocerebellar Ataxias) and TAMAHUD (Identification of Early Disease Markers, Novel Pharmacologically Tractable Targets and Small Molecule Phenotypic Modulators in Huntington's Disease)] and NIHR (National Institute of Health Research) Biomedical Research Centre (Addenbrooke's Hospital).

Abbreviations

     
  • BDNF

    brain-derived neurotrophic factor

  •  
  • CREB

    cAMP-response-element-binding protein

  •  
  • CBP

    CREB-binding protein

  •  
  • EGFP

    enhanced green fluorescent protein

  •  
  • ER

    endoplasmic reticulum

  •  
  • GIT1

    GPCR (G-protein-coupled receptor) kinase-interacting protein 1

  •  
  • GLT-1

    glutamate transporter-1

  •  
  • Hap

    huntingtin-associated protein

  •  
  • HD

    Huntington's disease

  •  
  • HDAC

    histone deacetylase

  •  
  • HEAT

    huntingtin, elongation factor 3, the PR65/A subunit of protein phosphatase 2A and the lipid kinase Tor

  •  
  • Hip

    huntingtin-interacting protein

  •  
  • hsp

    heat-shock protein

  •  
  • LMP

    low-molecular-mass polypeptide

  •  
  • MnSOD

    manganese superoxide dismutase

  •  
  • MSN

    medium spiny neuron

  •  
  • NES

    nuclear export signal

  •  
  • NLS

    nuclear localization signal

  •  
  • NMDA

    N-methyl-D-aspartate

  •  
  • NRSE

    neuron-restrictive silencer element

  •  
  • NRSF

    neuron-restrictive silencer factor

  •  
  • OGG1

    7,8-dihydro-8-oxoguanine-DNA glycosylase

  •  
  • 8-OHdG

    8-hydroxy-2′-deoxyguanosine

  •  
  • PGC-1α

    peroxisome-proliferator-activated receptor γ co-activator-1α

  •  
  • PSD

    postsynaptic density

  •  
  • REST

    repressor element-1 silencing transcription factor

  •  
  • ROS

    reactive oxygen species

  •  
  • SCA

    spinocerebellar ataxia

  •  
  • SH3

    Src homology 3

  •  
  • siRNA

    short interfering RNA

  •  
  • Sp1

    specificity protein 1

  •  
  • TAFII

    TBP-associated factor

  •  
  • TBP

    TATA-box-binding protein

  •  
  • TF

    transcription factor

  •  
  • UPS

    ubiquitin–proteasome system

References

References
1
Huntington
G.
On Chorea
Medical and Surgical Reporter
1872
, vol. 
vol. 26
 
Philadelphia
(pg. 
320
-
321
)
2
Water
C. O.
Dunglison
R.
Practice of Medicine
1842
, vol. 
vol. 2
 
Philadelphia
Lee and Blanchard
pg. 
312
 
3
Meynert
T.
Discussion to Fritsch
Psychiatry
1877
, vol. 
4
 pg. 
47
 
4
Jelgersma
G.
Die anatomischen Veranderungen bei. Paralysis agitans und chronischer Chorea
Verh. Ges. Dtsch. Naturforsch. Aerzte
1907
, vol. 
2
 (pg. 
383
-
388
)
5
Rosas
H. D.
Liu
A. K.
Hersch
S.
Glessner
M.
Ferrante
R. J.
Salat
D. H.
van der Kouwe
A.
Jenkins
B. G.
Dale
A. M.
Fischl
B.
Regional and progressive thinning of the cortical ribbon in Huntington's disease
Neurology
2002
, vol. 
58
 (pg. 
695
-
701
)
6
The Huntington's Disease Collaborative Research Group
A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes
Cell
1993
, vol. 
72
 (pg. 
971
-
983
)
7
Myers
R. H.
Huntington's disease genetics
NeuroRx
2004
, vol. 
1
 (pg. 
255
-
262
)
8
McNeil
S. M.
Novelletto
A.
Srinidhi
J.
Barnes
G.
Kornbluth
I.
Altherr
M. R.
Wasmuth
J. J.
Gusella
J. F.
MacDonald
M. E.
Myers
R. H.
Reduced penetrance of the Huntington's disease mutation
Hum. Mol. Genet.
1997
, vol. 
6
 (pg. 
775
-
779
)
9
Quarrell
O. W.
Rigby
A. S.
Barron
L.
Crow
Y.
Dalton
A.
Dennis
N.
Fryer
A. E.
Heydon
F.
Kinning
E.
Lashwood
A.
, et al. 
Reduced penetrance alleles for Huntington's disease: a multi-centre direct observational study
J. Med. Genet.
2007
, vol. 
44
 pg. 
e68
 
10
Ross
C. A.
When more is less: pathogenesis of glutamine repeat neurodegenerative diseases
Neuron
1995
, vol. 
15
 (pg. 
493
-
496
)
11
Rubinsztein
D. C.
Leggo
J.
Chiano
M.
Dodge
A.
Norbury
G.
Rosser
E.
Craufurd
D.
Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease
Proc. Natl. Acad. Sci. U.S.A.
1997
, vol. 
94
 (pg. 
3872
-
3876
)
12
MacDonald
M. E.
Vonsattel
J. P.
Shrinidhi
J.
Couropmitree
N. N.
Cupples
L. A.
Bird
E. D.
Gusella
J. F.
Myers
R. H.
Evidence for the GluR6 gene associated with younger onset age of Huntington's disease
Neurology
1999
, vol. 
53
 (pg. 
1330
-
1332
)
13
Kehoe
P.
Krawczak
M.
Harper
P. S.
Owen
M. J.
Jones
A. L.
Age of onset in Huntington disease: sex specific influence of apolipoprotein E genotype and normal CAG repeat length
J. Med. Genet.
1999
, vol. 
36
 (pg. 
108
-
111
)
14
Rosenblatt
A.
Brinkman
R. R.
Liang
K. Y.
Almqvist
E. W.
Margolis
R. L.
Huang
C. Y.
Sherr
M.
Franz
M. L.
Abbott
M. H.
Hayden
M. R.
Ross
C. A.
Familial influence on age of onset among siblings with Huntington disease
Am. J. Med. Genet.
2001
, vol. 
105
 (pg. 
399
-
403
)
15
Chattopadhyay
B.
Ghosh
S.
Gangopadhyay
P. K.
Das
S. K.
Roy
T.
Sinha
K. K.
Jha
D. K.
Mukherjee
S. C.
Chakraborty
A.
Singhal
B. S.
, et al. 
Modulation of age at onset in Huntington's disease and spinocerebellar ataxia type 2 patients originated from eastern India
Neurosci. Lett.
2003
, vol. 
345
 (pg. 
93
-
96
)
16
Chattopadhyay
B.
Baksi
K.
Mukhopadhyay
S.
Bhattacharyya
N. P.
Modulation of age at onset of Huntington disease patients by variations in TP53 and human caspase activated DNase (hCAD) genes
Neurosci. Lett.
2005
, vol. 
374
 (pg. 
81
-
86
)
17
Djousse
L.
Knowlton
B.
Hayden
M. R.
Almqvist
E. W.
Brinkman
R. R.
Ross
C. A.
Margolis
R. L.
Rosenblatt
A.
Durr
A.
Dode
C.
, et al. 
Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16
Neurogenetics
2004
, vol. 
5
 (pg. 
109
-
114
)
18
Wexler
N. S.
Lorimer
J.
Porter
J.
Gomez
F.
Moskowitz
C.
Shackell
E.
Marder
K.
Penchaszadeh
G.
Roberts
S. A.
Gayan
J.
, et al. 
Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset
Proc. Natl. Acad. Sci. U.S.A.
2004
, vol. 
101
 (pg. 
3498
-
3503
)
19
Ranen
N. G.
Stine
O. C.
Abbott
M. H.
Sherr
M.
Codori
A. M.
Franz
M. L.
Chao
N. I.
Chung
A. S.
Pleasant
N.
Callahan
C.
, et al. 
Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease
Am. J. Hum. Genet.
1995
, vol. 
57
 (pg. 
593
-
602
)
20
Kremer
B.
Almqvist
E.
Theilmann
J.
Spence
N.
Telenius
H.
Goldberg
Y. P.
Hayden
M. R.
Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes
Am. J. Hum. Genet.
1995
, vol. 
57
 (pg. 
343
-
350
)
21
Trottier
Y.
Biancalana
V.
Mandel
J. L.
Instability of CAG repeats in Huntington's disease: relation to parental transmission and age of onset
J. Med. Genet.
1994
, vol. 
31
 (pg. 
377
-
382
)
22
Gusella
J. F.
MacDonald
M. E.
Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease
Nat. Rev. Neurosci.
2000
, vol. 
1
 (pg. 
109
-
115
)
23
Maglione
V.
Cannella
M.
Gradini
R.
Cislaghi
G.
Squitieri
F.
Huntingtin fragmentation and increased caspase 3, 8 and 9 activities in lymphoblasts with heterozygous and homozygous Huntington's disease mutation
Mech. Ageing Dev.
2006
, vol. 
127
 (pg. 
213
-
216
)
24
Squitieri
F.
Gellera
C.
Cannella
M.
Mariotti
C.
Cislaghi
G.
Rubinsztein
D. C.
Almqvist
E. W.
Turner
D.
Bachoud-Levi
A. C.
Simpson
S. A.
, et al. 
Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course
Brain
2003
, vol. 
126
 (pg. 
946
-
955
)
25
Perutz
M. F.
Glutamine repeats and neurodegenerative diseases: molecular aspects
Trends Biochem. Sci.
1999
, vol. 
24
 (pg. 
58
-
63
)
26
Sugars
K. L.
Rubinsztein
D. C.
Transcriptional abnormalities in Huntington disease
Trends Genet.
2003
, vol. 
19
 (pg. 
233
-
238
)
27
Harper
P. S.
New genes for old diseases: the molecular basis of myotonic dystrophy and Huntington's disease. The Lumleian Lecture 1995
J. R. Coll. Phys. London
1996
, vol. 
30
 (pg. 
221
-
231
)
28
Ambrose
C. M.
Duyao
M. P.
Barnes
G.
Bates
G. P.
Lin
C. S.
Srinidhi
J.
Baxendale
S.
Hummerich
H.
Lehrach
H.
Altherr
M.
, et al. 
Structure and expression of the Huntington's disease gene: evidence against simple inactivation due to an expanded CAG repeat
Somat. Cell Mol. Genet.
1994
, vol. 
20
 (pg. 
27
-
38
)
29
Duyao
M. P.
Auerbach
A. B.
Ryan
A.
Persichetti
F.
Barnes
G. T.
McNeil
S. M.
Ge
P.
Vonsattel
J. P.
Gusella
J. F.
Joyner
A. L.
, et al. 
Inactivation of the mouse Huntington's disease gene homolog Hdh
Science
1995
, vol. 
269
 (pg. 
407
-
410
)
30
Nasir
J.
Floresco
S. B.
O'Kusky
J. R.
Diewert
V. M.
Richman
J. M.
Zeisler
J.
Borowski
A.
Marth
J. D.
Phillips
A. G.
Hayden
M. R.
Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes
Cell
1995
, vol. 
81
 (pg. 
811
-
823
)
31
Zeitlin
S.
Liu
J. P.
Chapman
D. L.
Papaioannou
V. E.
Efstratiadis
A.
Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue
Nat. Genet.
1995
, vol. 
11
 (pg. 
155
-
163
)
32
Marsh
J. L.
Walker
H.
Theisen
H.
Zhu
Y. Z.
Fielder
T.
Purcell
J.
Thompson
L. M.
Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila
Hum. Mol. Genet.
2000
, vol. 
9
 (pg. 
13
-
25
)
33
Ordway
J. M.
Tallaksen-Greene
S.
Gutekunst
C. A.
Bernstein
E. M.
Cearley
J. A.
Wiener
H. W.
Dure
L. S.
4th
Lindsey
R.
Hersch
S. M.
Jope
R. S.
, et al. 
Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse
Cell
1997
, vol. 
91
 (pg. 
753
-
763
)
34
Rubinsztein
D. C.
Lessons from animal models of Huntington's disease
Trends Genet.
2002
, vol. 
18
 (pg. 
202
-
209
)
35
Zuccato
C.
Ciammola
A.
Rigamonti
D.
Leavitt
B. R.
Goffredo
D.
Conti
L.
MacDonald
M. E.
Friedlander
R. M.
Silani
V.
Hayden
M. R.
, et al. 
Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease
Science
2001
, vol. 
293
 (pg. 
493
-
498
)
36
Reference deleted
37
Kegel
K. B.
Meloni
A. R.
Yi
Y.
Kim
Y. J.
Doyle
E.
Cuiffo
B. G.
Sapp
E.
Wang
Y.
Qin
Z. H.
Chen
J. D.
, et al. 
Huntingtin is present in the nucleus, interacts with the transcriptional corepressor C-terminal binding protein, and represses transcription
J. Biol. Chem.
2002
, vol. 
277
 (pg. 
7466
-
7476
)
38
Kegel
K. B.
Sapp
E.
Yoder
J.
Cuiffo
B.
Sobin
L.
Kim
Y. J.
Qin
Z.-H.
Hayden
M. R.
Aronin
N.
Scott
D. L.
, et al. 
Huntingtin associates with acidic phospholipids at the plasma membrane
J. Biol. Chem.
2005
, vol. 
280
 (pg. 
36464
-
36473
)
39
Caviston
J. P.
Ross
J. L.
Antony
S. M.
Tokito
M.
Holzbaur
E. L. F.
Huntingtin facilitates dynein/dynactin-mediated vesicle transport
Proc. Natl. Acad. Sci. U.S.A.
2007
, vol. 
104
 (pg. 
10045
-
10050
)
40
Strehlow
A. N. T.
Li
J. Z.
Myers
R. M.
Wild-type huntingtin participates in protein trafficking between the Golgi and the extracellular space
Hum. Mol. Genet.
2007
, vol. 
16
 (pg. 
391
-
409
)
41
Rockabrand
E.
Slepko
N.
Pantalone
A.
Nukala
V. N.
Kazantsev
A.
Marsh
J. L.
Sullivan
P. G.
Steffan
J. S.
Sensi
S. L.
Thompson
L. M.
The first 17 amino acids of huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis
Hum. Mol. Genet.
2007
, vol. 
16
 (pg. 
61
-
77
)
42
Atwal
R. S.
Xia
J.
Pinchev
D.
Taylor
J.
Epand
R. M.
Truant
R.
Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity
Hum. Mol. Genet.
2007
, vol. 
16
 (pg. 
2600
-
2615
)
43
Harjes
P.
Wanker
E. E.
The hunt for huntingtin function: interaction partners tell many different stories
Trends Biochem. Sci.
2003
, vol. 
28
 (pg. 
425
-
433
)
44
Li
S.-H.
Li
X.-J.
Huntingtin-protein interactions and the pathogenesis of Huntington's disease
Trends Genet.
2004
, vol. 
20
 (pg. 
146
-
154
)
45
Clabough
E. B. D.
Zeitlin
S. O.
Deletion of the triplet repeat encoding polyglutamine within the mouse Huntington's disease gene results in subtle behavioral/motor phenotypes in vivo and elevated levels of ATP with cellular senescence in vitro
Hum. Mol. Genet.
2006
, vol. 
15
 (pg. 
607
-
623
)
46
Li
W.
Serpell
L. C.
Carter
W. J.
Rubinsztein
D. C.
Huntington
J. A.
Expression and characterization of full-length human huntingtin, an elongated HEAT repeat protein
J. Biol. Chem.
2006
, vol. 
281
 (pg. 
15916
-
15922
)
47
Takano
H.
Gusella
J.
The predominantly HEAT-like motif structure of huntingtin and its association and coincident nuclear entry with dorsal, an NF-κB/Rel/dorsal family transcription factor
BMC Neurosci.
2002
, vol. 
3
 pg. 
15
 
48
Andrade
M. A.
Petosa
C.
O'Donoghue
S. I.
Muller
C. W.
Bork
P.
Comparison of ARM and HEAT protein repeats
J. Mol. Biol.
2001
, vol. 
309
 (pg. 
1
-
18
)
49
Perry
J.
Kleckner
N.
The ATRs, ATMs, and TORs are giant HEAT repeat proteins
Cell
2003
, vol. 
112
 (pg. 
151
-
155
)
50
Neuwald
A.
Hirano
T.
HEAT repeats associated with condensins, cohesins, and other complexes involved in chromosome-related functions
Genome Res.
2000
, vol. 
10
 (pg. 
1445
-
1452
)
51
Xia
J.
Lee
D.
Taylor
J.
Vandelft
M.
Truant
R.
Huntingtin contains a highly conserved nuclear export signal
Hum. Mol. Genet.
2003
, vol. 
12
 (pg. 
1393
-
1404
)
52
Cornett
J.
Cao
F.
Wang
C.-E.
Ross
C. A.
Bates
G. P.
Li
S.-H.
Li
X.-J.
Polyglutamine expansion of huntingtin impairs its nuclear export
2005
, vol. 
37
 (pg. 
198
-
204
)
53
Dohmen
R. J.
SUMO protein modification
Biochim. Biophys. Acta
2004
, vol. 
1695
 (pg. 
113
-
131
)
54
Steffan
J. S.
Agrawal
N.
Pallos
J.
Rockabrand
E.
Trotman
L. C.
Slepko
N.
Illes
K.
Lukacsovich
T.
Zhu
Y.-Z.
Cattaneo
E.
, et al. 
SUMO modification of huntingtin and Huntington's disease pathology
Science
2004
, vol. 
304
 (pg. 
100
-
104
)
55
Kalchman
M. A.
Graham
R. K.
Xia
G.
Koide
H. B.
Hodgson
J. G.
Graham
K. C.
Goldberg
Y. P.
Gietz
R. D.
Pickart
C. M.
Hayden
M. R.
Huntingtin is ubiquitinated and interacts with a specific ubiquitin-conjugating enzyme
J. Biol. Chem.
1996
, vol. 
271
 (pg. 
19385
-
19394
)
56
Huang
K.
Yanai
A.
Kang
R.
Arstikaitis
P.
Singaraja
R. R.
Metzler
M.
Mullard
A.
Haigh
B.
Gauthier-Campbell
C.
Gutekunst
C.-A.
, et al. 
Huntingtin-interacting protein HIP14 is a palmitoyl transferase involved in palmitoylation and trafficking of multiple neuronal proteins
Neuron
2004
, vol. 
44
 (pg. 
977
-
986
)
57
Yanai
A.
Huang
K.
Kang
R.
Singaraja
R. R.
Arstikaitis
P.
Gan
L.
Orban
P. C.
Mullard
A.
Cowan
C. M.
Raymond
L. A.
, et al. 
Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function
2006
, vol. 
9
 (pg. 
824
-
831
)
58
Kim
Y. J.
Yi
Y.
Sapp
E.
Wang
Y.
Cuiffo
B.
Kegel
K. B.
Qin
Z. H.
Aronin
N.
DiFiglia
M.
Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis
Proc. Natl. Acad. Sci. U.S.A.
2001
, vol. 
98
 (pg. 
12784
-
12789
)
59
Gafni
J.
Ellerby
L. M.
Calpain activation in Huntington's disease
J. Neurosci.
2002
, vol. 
22
 (pg. 
4842
-
4849
)
60
Wellington
C. L.
Ellerby
L. M.
Gutekunst
C. A.
Rogers
D.
Warby
S.
Graham
R. K.
Loubser
O.
van Raamsdonk
J.
Singaraja
R.
Yang
Y. Z.
, et al. 
Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease
J. Neurosci.
2002
, vol. 
22
 (pg. 
7862
-
7872
)
61
Lunkes
A.
Lindenberg
K. S.
Ben-Haiem
L.
Weber
C.
Devys
D.
Landwehrmeyer
G. B.
Mandel
J. L.
Trottier
Y.
Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions
Mol. Cell
2002
, vol. 
10
 (pg. 
259
-
269
)
62
Hermel
E.
Gafni
J.
Propp
S. S.
Leavitt
B. R.
Wellington
C. L.
Young
J. E.
Hackam
A. S.
Logvinova
A. V.
Peel
A. L.
Chen
S. F.
, et al. 
Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease
Cell Death Differ.
2004
, vol. 
11
 (pg. 
424
-
438
)
63
Gafni
J.
Hermel
E.
Young
J. E.
Wellington
C. L.
Hayden
M. R.
Ellerby
L. M.
Inhibition of calpain cleavage of huntingtin reduces toxicity: accumulation of calpain/caspase fragments in the nucleus
J. Biol. Chem.
2004
, vol. 
279
 (pg. 
20211
-
20220
)
64
Graham
R. K.
Deng
Y.
Slow
E. J.
Haigh
B.
Bissada
N.
Lu
G.
Pearson
J.
Shehadeh
J.
Bertram
L.
Murphy
Z.
, et al. 
Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin
Cell
2006
, vol. 
125
 (pg. 
1179
-
1191
)
65
Kaltenbach
L. S.
Romero
E.
Becklin
R. R.
Chettier
R.
Bell
R.
Phansalkar
A.
Strand
A.
Torcassi
C.
Savage
J.
Hurlburt
A.
, et al. 
Huntingtin interacting proteins are genetic modifiers of neurodegeneration
PLoS Genet.
2007
, vol. 
3
 pg. 
e82
 
66
Borrell-Pages
M.
Zala
D.
Humbert
S.
Saudou
F.
Huntington's disease: from huntingtin function and dysfunction to therapeutic strategies
Cell. Mol. Life Sci.
2006
, vol. 
63
 (pg. 
2642
-
2660
)
67
Lumsden
A. L.
Henshall
T. L.
Dayan
S.
Lardelli
M. T.
Richards
R. I.
Huntingtin-deficient zebrafish exhibit defects in iron utilization and development
Hum. Mol. Genet.
2007
, vol. 
16
 (pg. 
1905
-
1920
)
68
Dragatsis
I.
Levine
M. S.
Zeitlin
S.
Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice
Nat. Genet.
2000
, vol. 
26
 (pg. 
300
-
306
)
69
Rigamonti
D.
Sipione
S.
Goffredo
D.
Zuccato
C.
Fossale
E.
Cattaneo
E.
Huntingtin's neuroprotective activity occurs via inhibition of procaspase-9 processing
J. Biol. Chem.
2001
, vol. 
276
 (pg. 
14545
-
14548
)
70
Ho
L. W.
Brown
R.
Maxwell
M.
Wyttenbach
A.
Rubinsztein
D. C.
Wild type huntingtin reduces the cellular toxicity of mutant huntingtin in mammalian cell models of Huntington's disease
J. Med. Genet.
2001
, vol. 
38
 (pg. 
450
-
452
)
71
Rigamonti
D.
Bauer
J. H.
De-Fraja
C.
Conti
L.
Sipione
S.
Sciorati
C.
Clementi
E.
Hackam
A.
Hayden
M. R.
Li
Y.
, et al. 
Wild-type huntingtin protects from apoptosis upstream of caspase-3
J. Neurosci.
2000
, vol. 
20
 (pg. 
3705
-
3713
)
72
Gervais
F. G.
Singaraja
R.
Xanthoudakis
S.
Gutekunst
C. A.
Leavitt
B. R.
Metzler
M.
Hackam
A. S.
Tam
J.
Vaillancourt
J. P.
Houtzager
V.
, et al. 
Recruitment and activation of caspase-8 by the huntingtin-interacting protein Hip-1 and a novel partner HIPPI
Nat. Cell Biol.
2002
, vol. 
4
 (pg. 
95
-
105
)
73
Zhang
Y.
Leavitt
B. R.
van Raamsdonk
J. M.
Dragatsis
I.
Goldowitz
D.
MacDonald
M. E.
Hayden
M. R.
Friedlander
R. M.
Huntingtin inhibits caspase-3 activation
EMBO J.
2006
, vol. 
25
 (pg. 
5896
-
5906
)
74
Faber
P.
Barnes
G.
Srinidhi
J.
Chen
J.
Gusella
J.
MacDonald
M.
Huntingtin interacts with a family of WW domain proteins
Hum. Mol. Genet.
1998
, vol. 
7
 (pg. 
1463
-
1474
)
75
Truant
R.
Atwal
R. S.
Burtnik
A.
Nucleocytoplasmic trafficking and transcription effects of huntingtin in Huntington's disease
Prog. Neurobiol.
2007
, vol. 
83
 (pg. 
211
-
227
)
76
Zuccato
C.
Tartari
M.
Crotti
A.
Goffredo
D.
Valenza
M.
Conti
L.
Cataudella
T.
Leavitt
B. R.
Hayden
M. R.
Timmusk
T.
, et al. 
Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes
2003
, vol. 
35
 (pg. 
76
-
83
)
77
Smith
R.
Brundin
P.
Li
J. Y.
Synaptic dysfunction in Huntington's disease: a new perspective
Cell. Mol. Life Sci.
2005
, vol. 
62
 (pg. 
1901
-
1912
)
78
Gauthier
L. R.
Charrin
B. C.
Borrell-Pages
M.
Dompierre
J. P.
Rangone
H.
Cordelieres
F. P.
De Mey
J.
MacDonald
M. E.
Lessmann
V.
, et al. 
Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules
Cell
2004
, vol. 
118
 (pg. 
127
-
138
)
79
Gunawardena
S.
Her
L. S.
Brusch
R. G.
Laymon
R. A.
Niesman
I. R.
Gordesky-Gold
B.
Sintasath
L.
Bonini
N. M.
Goldstein
L. S.
Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila
Neuron
2003
, vol. 
40
 (pg. 
25
-
40
)
80
Pal
A.
Severin
F.
Lommer
B.
Shevchenko
A.
Zerial
M.
Huntingtin–HAP40 complex is a novel Rab5 effector that regulates early endosome motility and is up-regulated in Huntington's disease
J. Cell Biol.
2006
, vol. 
172
 (pg. 
605
-
618
)
81
Trushina
E.
Dyer
R. B.
Badger
J. D.
2nd
Ure
D.
Eide
L.
Tran
D. D.
Vrieze
B. T.
Legendre-Guillemin
V.
McPherson
P. S.
Mandavilli
B. S.
, et al. 
Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro
Mol. Cell. Biol.
2004
, vol. 
24
 (pg. 
8195
-
8209
)
82
McGuire
J. R.
Rong
J.
Li
S.-H.
Li
X.-J.
Interaction of huntingtinassociated protein-1 with kinesin light chain: implications in intracellular trafficking in neurons
J. Biol. Chem.
2006
, vol. 
281
 (pg. 
3552
-
3559
)
83
Fan
M. M.
Raymond
L. A.
N-methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington's disease
Prog. Neurobiol.
2007
, vol. 
81
 (pg. 
272
-
293
)
84
Sun
Y.
Savanenin
A.
Reddy
P. H.
Liu
Y. F.
Polyglutamine-expanded huntingtin promotes sensitization of N-methyl-D-aspartate receptors via post-synaptic density 95
J. Biol. Chem.
2001
, vol. 
276
 (pg. 
24713
-
24718
)
85
Kim
J. H.
Liao
D.
Lau
L. F.
Huganir
R. L.
SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family
Neuron
1998
, vol. 
20
 (pg. 
683
-
691
)
86
Anborgh
P. H.
Godin
C.
Pampillo
M.
Dhami
G. K.
Dale
L. B.
Cregan
S. P.
Truant
R.
Ferguson
S. S.
Inhibition of metabotropic glutamate receptor signaling by the huntingtin-binding protein optineurin
J. Biol. Chem.
2005
, vol. 
280
 (pg. 
34840
-
34848
)
87
Davies
S. W.
Turmaine
M.
Cozens
B. A.
DiFiglia
M.
Sharp
A. H.
Ross
C. A.
Scherzinger
E.
Wanker
E. E.
Mangiarini
L.
Bates
G. P.
Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation
Cell
1997
, vol. 
90
 (pg. 
537
-
548
)
88
Schilling
G.
Becher
M. W.
Sharp
A. H.
Jinnah
H. A.
Duan
K.
Kotzuk
J. A.
Slunt
H. H.
Ratovitski
T.
Cooper
J. K.
Jenkins
N. A.
, et al. 
Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin
Hum. Mol. Genet.
1999
, vol. 
8
 (pg. 
397
-
407
)
89
Palfi
S.
Brouillet
E.
Jarraya
B.
Bloch
J.
Jan
C.
Shin
M.
Conde
F.
Li
X. J.
Aebischer
P.
Hantraye
P.
Deglon
N.
Expression of mutated huntingtin fragment in the putamen is sufficient to produce abnormal movement in non-human primates
Mol. Ther.
2007
, vol. 
15
 (pg. 
1444
-
1451
)
90
Wellington
C. L.
Ellerby
L. M.
Hackam
A. S.
Margolis
R. L.
Trifiro
M. A.
Singaraja
R.
McCutcheon
K.
Salvesen
G. S.
Propp
S. S.
Bromm
M.
, et al. 
Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract
J. Biol. Chem.
1998
, vol. 
273
 (pg. 
9158
-
9167
)
91
Luo
S.
Vacher
C.
Davies
J. E.
Rubinsztein
D. C.
Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity
J. Cell Biol.
2005
, vol. 
169
 (pg. 
647
-
656
)
92
Humbert
S.
Bryson
E. A.
Cordelieres
F. P.
Connors
N. C.
Datta
S. R.
Finkbeiner
S.
Greenberg
M. E.
Saudou
F.
The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves huntingtin phosphorylation by Akt
Dev. Cell
2002
, vol. 
2
 (pg. 
831
-
837
)
93
Schilling
B.
Gafni
J.
Torcassi
C.
Cong
X.
Row
R. H.
LaFevre-Bernt
M. A.
Cusack
M. P.
Ratovitski
T.
Hirschhorn
R.
Ross
C. A.
, et al. 
Huntingtin phosphorylation sites mapped by mass spectrometry: modulation of cleavage and toxicity
J. Biol. Chem.
2006
, vol. 
281
 (pg. 
23686
-
23697
)
94
Tanaka
Y.
Igarashi
S.
Nakamura
M.
Gafni
J.
Torcassi
C.
Schilling
G.
Crippen
D.
Wood
J. D.
Sawa
A.
Jenkins
N. A.
, et al. 
Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin
Neurobiol. Dis.
2006
, vol. 
21
 (pg. 
381
-
391
)
95
DiFiglia
M.
Sapp
E.
Chase
K. O.
Davies
S. W.
Bates
G. P.
Vonsattel
J. P.
Aronin
N.
Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain
Science
1997
, vol. 
277
 (pg. 
1990
-
1993
)
96
Becher
M. W.
Kotzuk
J. A.
Sharp
A. H.
Davies
S. W.
Bates
G. P.
Price
D. L.
Ross
C. A.
Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length
Neurobiol. Dis.
1998
, vol. 
4
 (pg. 
387
-
397
)
97
Gutekunst
C. A.
Li
S. H.
Yi
H.
Mulroy
J. S.
Kuemmerle
S.
Jones
R.
Rye
D.
Ferrante
R. J.
Hersch
S. M.
Li
X. J.
Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology
J. Neurosci.
1999
, vol. 
19
 (pg. 
2522
-
2534
)
98
Kuemmerle
S.
Gutekunst
C. A.
Klein
A. M.
Li
X. J.
Li
S. H.
Beal
M. F.
Hersch
S. M.
Ferrante
R. J.
Huntington aggregates may not predict neuronal death in Huntington's disease
Ann. Neurol.
1999
, vol. 
46
 (pg. 
842
-
849
)
99
Hackam
A. S.
Singaraja
R.
Wellington
C. L.
Metzler
M.
McCutcheon
K.
Zhang
T.
Kalchman
M.
Hayden
M. R.
The influence of huntingtin protein size on nuclear localization and cellular toxicity
J. Cell Biol.
1998
, vol. 
141
 (pg. 
1097
-
1105
)
100
Wyttenbach
A.
Carmichael
J.
Swartz
J.
Furlong
R. A.
Narain
Y.
Rankin
J.
Rubinsztein
D. C.
Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease
Proc. Natl. Acad. Sci. U.S.A.
2000
, vol. 
97
 (pg. 
2898
-
2903
)
101
Lunkes
A.
Mandel
J. L.
A cellular model that recapitulates major pathogenic steps of Huntington's disease
Hum. Mol. Genet.
1998
, vol. 
7
 (pg. 
1355
-
1361
)
102
Morton
A. J.
Lagan
M. A.
Skepper
J. N.
Dunnett
S. B.
Progressive formation of inclusions in the striatum and hippocampus of mice transgenic for the human Huntington's disease mutation
J. Neurocytol.
2000
, vol. 
29
 (pg. 
679
-
702
)
103
Tam
S.
Geller
R.
Spiess
C.
Frydman
J.
The chaperonin TRiC controls polyglutamine aggregation and toxicity through subunit-specific interactions
Nat. Cell Biol.
2006
, vol. 
8
 (pg. 
1155
-
1162
)
104
Mitsui
K.
Nakayama
H.
Akagi
T.
Nekooki
M.
Ohtawa
K.
Takio
K.
Hashikawa
T.
Nukina
N.
Purification of polyglutamine aggregates and identification of elongation factor-1α and heat shock protein 84 as aggregate-interacting proteins
J. Neurosci.
2002
, vol. 
22
 (pg. 
9267
-
9277
)
105
Kitamura
A.
Kubota
H.
Pack
C. G.
Matsumoto
G.
Hirayama
S.
Takahashi
Y.
Kimura
H.
Kinjo
M.
Morimoto
R. I.
Nagata
K.
Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state
Nat. Cell Biol.
2006
, vol. 
8
 (pg. 
1163
-
1170
)
106
Jana
N. R.
Dikshit
P.
Goswami
A.
Kotliarova
S.
Murata
S.
Tanaka
K.
Nukina
N.
Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes
J. Biol. Chem.
2005
, vol. 
280
 (pg. 
11635
-
11640
)
107
Chuang
J. Z.
Zhou
H.
Zhu
M.
Li
S. H.
Li
X. J.
Sung
C. H.
Characterization of a brain-enriched chaperone, MRJ, that inhibits huntingtin aggregation and toxicity independently
J. Biol. Chem.
2002
, vol. 
277
 (pg. 
19831
-
19838
)
108
Jana
N. R.
Tanaka
M.
Wang
G.
Nukina
N.
Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity
Hum. Mol. Genet.
2000
, vol. 
9
 (pg. 
2009
-
2018
)
109
Vacher
C.
Garcia-Oroz
L.
Rubinsztein
D. C.
Overexpression of yeast hsp104 reduces polyglutamine aggregation and prolongs survival of a transgenic mouse model of Huntington's disease
Hum. Mol. Genet.
2005
, vol. 
14
 (pg. 
3425
-
3433
)
110
Carmichael
J.
Chatellier
J.
Woolfson
A.
Milstein
C.
Fersht
A. R.
Rubinsztein
D. C.
Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease
Proc. Natl. Acad. Sci. U.S.A.
2000
, vol. 
97
 (pg. 
9701
-
9705
)
111
Wyttenbach
A.
Sauvageot
O.
Carmichael
J.
Diaz-Latoud
C.
Arrigo
A. P.
Rubinsztein
D. C.
Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin
Hum. Mol. Genet.
2002
, vol. 
11
 (pg. 
1137
-
1151
)
112
Goswami
A.
Dikshit
P.
Mishra
A.
Mulherkar
S.
Nukina
N.
Jana
N. R.
Oxidative stress promotes mutant huntingtin aggregation and mutant huntingtin-dependent cell death by mimicking proteasomal malfunction
Biochem. Biophys. Res. Commun.
2006
, vol. 
342
 (pg. 
184
-
190
)
113
Schiffer
N. W.
Broadley
S. A.
Hirschberger
T.
Tavan
P.
Kretzschmar
H. A.
Giese
A.
Haass
C.
Hartl
F. U.
Schmid
B.
Identification of anti-prion compounds as efficient inhibitors of polyglutamine protein aggregation in a zebrafish model
J. Biol. Chem.
2007
, vol. 
282
 (pg. 
9195
-
9203
)
114
Mastroberardino
P. G.
Iannicola
C.
Nardacci
R.
Bernassola
F.
De Laurenzi
V.
Melino
G.
Moreno
S.
Pavone
F.
Oliverio
S.
Fesus
L.
Piacentini
M.
‘Tissue’ transglutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Huntington's disease
Cell Death Differ.
2002
, vol. 
9
 (pg. 
873
-
880
)
115
Arango
M.
Holbert
S.
Zala
D.
Brouillet
E.
Pearson
J.
Regulier
E.
Thakur
A. K.
Aebischer
P.
Wetzel
R.
Deglon
N.
Neri
C.
CA150 expression delays striatal cell death in overexpression and knock-in conditions for mutant huntingtin neurotoxicity
J. Neurosci.
2006
, vol. 
26
 (pg. 
4649
-
4659
)
116
Bodner
R. A.
Outeiro
T. F.
Altmann
S.
Maxwell
M. M.
Cho
S. H.
Hyman
B. T.
McLean
P. J.
Young
A. B.
Housman
D. E.
Kazantsev
A. G.
Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington's and Parkinson's diseases
Proc. Natl. Acad. Sci. U.S.A.
2006
, vol. 
103
 (pg. 
4246
-
4251
)
117
Arrasate
M.
Mitra
S.
Schweitzer
E. S.
Segal
M. R.
Finkbeiner
S.
Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death
Nature
2004
, vol. 
431
 (pg. 
805
-
810
)
118
Martindale
D.
Hackam
A.
Wieczorek
A.
Ellerby
L.
Wellington
C.
McCutcheon
K.
Singaraja
R.
Kazemi-Esfarjani
P.
Devon
R.
Kim
S. U.
, et al. 
Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates
Nat. Genet.
1998
, vol. 
18
 (pg. 
150
-
154
)
119
Saudou
F.
Finkbeiner
S.
Devys
D.
Greenberg
M. E.
Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions
Cell
1998
, vol. 
95
 (pg. 
55
-
66
)
120
Ross
C. A.
Poirier
M. A.
Protein aggregation and neurodegenerative disease
Nat. Med.
2004
, vol. 
10
 
Suppl.
(pg. 
S10
-
S17
)
121
Schilling
G.
Savonenko
A. V.
Klevytska
A.
Morton
J. L.
Tucker
S. M.
Poirier
M.
Gale
A.
Chan
N.
Gonzales
V.
Slunt
H. H.
Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice
Hum. Mol. Genet.
2004
, vol. 
13
 (pg. 
1599
-
1610
)
122
Perutz
M. F.
Johnson
T.
Suzuki
M.
Finch
J. T.
Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases
Proc. Natl. Acad. Sci. U.S.A.
1994
, vol. 
91
 (pg. 
5355
-
5358
)
123
Gerber
H. P.
Seipel
K.
Georgiev
O.
Hofferer
M.
Hug
M.
Rusconi
S.
Schaffner
W.
Transcriptional activation modulated by homopolymeric glutamine and proline stretches
Science
1994
, vol. 
263
 (pg. 
808
-
811
)
124
Kazantsev
A.
Preisinger
E.
Dranovsky
A.
Goldgaber
D.
Housman
D.
Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells
Proc. Natl. Acad. Sci. U.S.A.
1999
, vol. 
96
 (pg. 
11404
-
11409
)
125
Nucifora
F. C.
Jr
Sasaki
M.
Peters
M. F.
Huang
H.
Cooper
J. K.
Yamada
M.
Takahashi
H.
Tsuji
S.
Troncoso
J.
Dawson
V. L.
, et al. 
Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity
Science
2001
, vol. 
291
 (pg. 
2423
-
2428
)
126
Steffan
J. S.
Kazantsev
A.
Spasic-Boskovic
O.
Greenwald
M.
Zhu
Y. Z.
Gohler
H.
Wanker
E. E.
Bates
G. P.
Housman
D. E.
Thompson
L. M.
The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription
Proc. Natl. Acad. Sci. U.S.A.
2000
, vol. 
97
 (pg. 
6763
-
6768
)
127
Steffan
J. S.
Bodai
L.
Pallos
J.
Poelman
M.
McCampbell
A.
Apostol
B. L.
Kazantsev
A.
Schmidt
E.
Zhu
Y. Z.
Greenwald
M.
, et al. 
Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila
Nature
2001
, vol. 
413
 (pg. 
739
-
743
)
128
McCampbell
A.
Taye
A. A.
Whitty
L.
Penney
E.
Steffan
J. S.
Fischbeck
K. H.
Histone deacetylase inhibitors reduce polyglutamine toxicity
Proc. Natl. Acad. Sci. U.S.A.
2001
, vol. 
98
 (pg. 
15179
-
15184
)
129
Hughes
R. E.
Lo
R. S.
Davis
C.
Strand
A. D.
Neal
C. L.
Olson
J. M.
Fields
S.
Altered transcription in yeast expressing expanded polyglutamine
Proc. Natl. Acad. Sci. U.S.A.
2001
, vol. 
98
 (pg. 
13201
-
13206
)
130
Ferrante
R. J.
Kubilus
J. K.
Lee
J.
Ryu
H.
Beesen
A.
Zucker
B.
Smith
K.
Kowall
N. W.
Ratan
R. R.
Luthi-Carter
R.
Hersch
S. M.
Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice
J. Neurosci.
2003
, vol. 
23
 (pg. 
9418
-
9427
)
131
Hockly
E.
Richon
V. M.
Woodman
B.
Smith
D. L.
Zhou
X.
Rosa
E.
Sathasivam
K.
Ghazi-Noori
S.
Mahal
A.
Lowden
P. A.
, et al. 
Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease
Proc. Natl. Acad. Sci. U.S.A.
2003
, vol. 
100
 (pg. 
2041
-
2046
)
132
Tanese
N.
Tjian
R.
Coactivators and TAFs: a new class of eukaryotic transcription factors that connect activators to the basal machinery
Cold Spring Harbor Symp. Quant. Biol.
1993
, vol. 
58
 (pg. 
179
-
185
)
133
Yu
Z. X.
Li
S. H.
Nguyen
H. P.
Li
X. J.
Huntingtin inclusions do not deplete polyglutamine-containing transcription factors in HD mice
Hum. Mol. Genet.
2002
, vol. 
11
 (pg. 
905
-
914
)
134
Dunah
A. W.
Jeong
H.
Griffin
A.
Kim
Y. M.
Standaert
D. G.
Hersch
S. M.
Mouradian
M. M.
Young
A. B.
Tanese
N.
Krainc
D.
Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease
Science
2002
, vol. 
296
 (pg. 
2238
-
2243
)
135
Qiu
Z.
Norflus
F.
Singh
B.
Swindell
M. K.
Buzescu
R.
Bejarano
M.
Chopra
R.
Zucker
B.
Benn
C. L.
DiRocco
D. P.
, et al. 
Sp1 is up-regulated in cellular and transgenic models of Huntington disease, and its reduction is neuroprotective
J. Biol. Chem.
2006
, vol. 
281
 (pg. 
16672
-
16680
)
136
Zhai
W.
Jeong
H.
Cui
L.
Krainc
D.
Tjian
R.
In vitro analysis of huntingtin-mediated transcriptional repression reveals multiple transcription factor targets
Cell
2005
, vol. 
123
 (pg. 
1241
-
1253
)
137
Hodgson
J. G.
Agopyan
N.
Gutekunst
C. A.
Leavitt
B. R.
LePiane
F.
Singaraja
R.
Smith
D. J.
Bissada
N.
McCutcheon
K.
Nasir
J.
, et al. 
A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration
Neuron
1999
, vol. 
23
 (pg. 
181
-
192
)
138
Chong
J. A.
Tapia-Ramirez
J.
Kim
S.
Toledo-Aral
J. J.
Zheng
Y.
Boutros
M. C.
Altshuller
Y. M.
Frohman
M. A.
Kraner
S. D.
Mandel
G.
REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons
Cell
1995
, vol. 
80
 (pg. 
949
-
957
)
139
Reference deleted
140
Schoenherr
C. J.
Anderson
D. J.
The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes
Science
1995
, vol. 
267
 (pg. 
1360
-
1363
)
141
Puigserver
P.
Wu
Z.
Park
C. W.
Graves
R.
Wright
M.
Spiegelman
B. M.
A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis
Cell
1998
, vol. 
92
 (pg. 
829
-
839
)
142
Puigserver
P.
Spiegelman
B. M.
Peroxisome proliferator activated receptor-γ coactivator 1α (PGC-1α): transcriptional coactivator and metabolic regulator
Endocr. Rev.
2003
, vol. 
24
 (pg. 
78
-
90
)
143
Lin
J.
Wu
H.
Tarr
P. T.
Zhang
C. Y.
Wu
Z.
Boss
O.
Michael
L. F.
Puigserver
P.
Isotani
E.
Olson
E. N.
, et al. 
Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres
Nature
2002
, vol. 
418
 (pg. 
797
-
801
)
144
Leone
T. C.
Lehman
J. J.
Finck
B. N.
Schaeffer
P. J.
Wende
A. R.
Boudina
S.
Courtois
M.
Wozniak
D. F.
Sambandam
N.
Bernal-Mizrachi
C.
, et al. 
PGC-1α deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis
PLoS Biol.
2005
, vol. 
3
 pg. 
e101
 
145
Cui
L.
Jeong
H.
Borovecki
F.
Parkhurst
C. N.
Tanese
N.
Krainc
D.
Transcriptional repression of PGC-1α by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration
Cell
2006
, vol. 
127
 (pg. 
59
-
69
)
146
Weydt
P.
Pineda
V. V.
Torrence
A. E.
Libby
R. T.
Satterfield
T. F.
Lazarowski
E. R.
Gilbert
M. L.
Morton
G. J.
Bammler
T. K.
Strand
A. D.
, et al. 
Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1α in Huntington's disease neurodegeneration
Cell Metab.
2006
, vol. 
4
 (pg. 
349
-
362
)
147
Trushina
E.
McMurray
C. T.
Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases
Neuroscience
2007
, vol. 
145
 (pg. 
1233
-
1248
)
148
Lin
M. T.
Beal
M. F.
Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases
Nature
2006
, vol. 
443
 (pg. 
787
-
795
)
149
Beal
M. F.
Mitochondria take center stage in aging and neurodegeneration
Ann. Neurol.
2005
, vol. 
58
 (pg. 
495
-
505
)
150
Raha
S.
Robinson
B. H.
Mitochondria, oxygen free radicals, disease and ageing
Trends Biochem. Sci.
2000
, vol. 
25
 (pg. 
502
-
508
)
151
Chance
B.
Sies
H.
Boveris
A.
Hydroperoxide metabolism in mammalian organs
Physiol. Rev.
1979
, vol. 
59
 (pg. 
527
-
605
)
152
Guidot
D. M.
McCord
J. M.
Wright
R. M.
Repine
J. E.
Absence of electron transport (Rho 0 state) restores growth of a manganese superoxide dismutase-deficient Saccharomyces cerevisiae in hyperoxia: evidence for electron transport as a major source of superoxide generation in vivo
J. Biol. Chem.
1993
, vol. 
268
 (pg. 
26699
-
26703
)
153
Floyd
R. A.
Carney
J. M.
Free radical damage to protein and DNA: mechanisms involved and relevant observations on brain undergoing oxidative stress
Ann. Neurol.
1992
, vol. 
32
 
Suppl.
(pg. 
S22
-
S27
)
154
Huie
R. E.
Padmaja
S.
The reaction of NO with superoxide
Free Radical Res. Commun.
1993
, vol. 
18
 (pg. 
195
-
199
)
155
Radi
R.
Rodriguez
M.
Castro
L.
Telleri
R.
Inhibition of mitochondrial electron transport by peroxynitrite
Arch. Biochem. Biophys.
1994
, vol. 
308
 (pg. 
89
-
95
)
156
Castro
L.
Rodriguez
M.
Radi
R.
Aconitase is readily inactivated by peroxynitrite, but not by its precursor, nitric oxide
J. Biol. Chem.
1994
, vol. 
269
 (pg. 
29409
-
29415
)
157
MacMillan-Crow
L. A.
Crow
J. P.
Thompson
J. A.
Peroxynitrite-mediated inactivation of manganese superoxide dismutase involves nitration and oxidation of critical tyrosine residues
Biochemistry
1998
, vol. 
37
 (pg. 
1613
-
1622
)
158
Imlay
J. A.
Pathways of oxidative damage
Annu. Rev. Microbiol.
2003
, vol. 
57
 (pg. 
395
-
418
)
159
Gardner
P. R.
Raineri
I.
Epstein
L. B.
White
C. W.
Superoxide radical and iron modulate aconitase activity in mammalian cells
J. Biol. Chem.
1995
, vol. 
270
 (pg. 
13399
-
13405
)
160
Balaban
R. S.
Nemoto
S.
Finkel
T.
Mitochondria, oxidants, and aging
Cell
2005
, vol. 
120
 (pg. 
483
-
495
)
161
Finkel
T.
Oxidant signals and oxidative stress
Curr. Opin. Cell Biol.
2003
, vol. 
15
 (pg. 
247
-
254
)
162
Sohal
R. S.
Role of oxidative stress and protein oxidation in the aging process
Free Radical Biol. Med.
2002
, vol. 
33
 (pg. 
37
-
44
)
163
Browne
S. E.
Beal
M. F.
The energetics of Huntington's disease
Neurochem. Res.
2004
, vol. 
29
 (pg. 
531
-
546
)
164
Tabrizi
S. J.
Cleeter
M. W.
Xuereb
J.
Taanman
J. W.
Cooper
J. M.
Schapira
A. H.
Biochemical abnormalities and excitotoxicity in Huntington's disease brain
Ann. Neurol.
1999
, vol. 
45
 (pg. 
25
-
32
)
165
Mangiarini
L.
Sathasivam
K.
Seller
M.
Cozens
B.
Harper
A.
Hetherington
C.
Lawton
M.
Trottier
Y.
Lehrach
H.
Davies
S. W.
Bates
G. P.
Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice
Cell
1996
, vol. 
87
 (pg. 
493
-
506
)
166
Saft
C.
Zange
J.
Andrich
J.
Muller
K.
Lindenberg
K.
Landwehrmeyer
B.
Vorgerd
M.
Kraus
P. H.
Przuntek
H.
Schols
L.
Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington's disease
Mov. Disord.
2005
, vol. 
20
 (pg. 
674
-
679
)
167
Orth
M.
Schapira
A. H.
Mitochondria and degenerative disorders
Am. J. Med. Genet.
2001
, vol. 
106
 (pg. 
27
-
36
)
168
Choo
Y. S.
Johnson
G. V.
MacDonald
M.
Detloff
P. J.
Lesort
M.
Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release
Hum. Mol. Genet.
2004
, vol. 
13
 (pg. 
1407
-
1420
)
169
Panov
A. V.
Burke
J. R.
Strittmatter
W. J.
Greenamyre
J. T.
In vitro effects of polyglutamine tracts on Ca2+-dependent depolarization of rat and human mitochondria: relevance to Huntington's disease
Arch. Biochem. Biophys.
2003
, vol. 
410
 (pg. 
1
-
6
)
170
Panov
A. V.
Gutekunst
C. A.
Leavitt
B. R.
Hayden
M. R.
Burke
J. R.
Strittmatter
W. J.
Greenamyre
J. T.
Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines
Nat. Neurosci.
2002
, vol. 
5
 (pg. 
731
-
736
)
171
Sawa
A.
Wiegand
G. W.
Cooper
J.
Margolis
R. L.
Sharp
A. H.
Lawler
J. F.
Jr
Greenamyre
J. T.
Snyder
S. H.
Ross
C. A.
Increased apoptosis of Huntington disease lymphoblasts associated with repeat length dependent mitochondrial depolarization
Nat. Med.
1999
, vol. 
5
 (pg. 
1194
-
1198
)
172
Carafoli
E.
Historical review: mitochondria and calcium: ups and downs of an unusual relationship
Trends Biochem. Sci.
2003
, vol. 
28
 (pg. 
175
-
181
)
173
Orrenius
S.
Zhivotovsky
B.
Nicotera
P.
Regulation of cell death: the calcium–apoptosis link
Nat. Rev. Mol. Cell Biol.
2003
, vol. 
4
 (pg. 
552
-
565
)
174
Seong
I. S.
Ivanova
E.
Lee
J. M.
Choo
Y. S.
Fossale
E.
Anderson
M.
Gusella
J. F.
Laramie
J. M.
Myers
R. H.
Lesort
M.
MacDonald
M. E.
HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism
Hum. Mol. Genet.
2005
, vol. 
14
 (pg. 
2871
-
2880
)
175
Novelli
A.
Reilly
J. A.
Lysko
P. G.
Henneberry
R. C.
Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced
Brain Res.
1988
, vol. 
451
 (pg. 
205
-
212
)
176
Fagni
L.
Lafon-Cazal
M.
Rondouin
G.
Manzoni
O.
Lerner-Natoli
M.
Bockaert
J.
The role of free radicals in NMDA-dependent neurotoxicity
Prog. Brain Res.
1994
, vol. 
103
 (pg. 
381
-
390
)
177
Zeron
M. M.
Fernandes
H. B.
Krebs
C.
Shehadeh
J.
Wellington
C. L.
Leavitt
B. R.
Baimbridge
K. G.
Hayden
M. R.
Raymond
L. A.
Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic apoptotic pathway in YAC transgenic mouse model of Huntington's disease
Mol. Cell. Neurosci.
2004
, vol. 
25
 (pg. 
469
-
479
)
178
Zeron
M. M.
Hansson
O.
Chen
N.
Wellington
C. L.
Leavitt
B. R.
Brundin
P.
Hayden
M. R.
Raymond
L. A.
Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease
Neuron
2002
, vol. 
33
 (pg. 
849
-
860
)
179
Lafon-Cazal
M.
Pietri
S.
Culcasi
M.
Bockaert
J.
NMDA-dependent superoxide production and neurotoxicity
Nature
1993
, vol. 
364
 (pg. 
535
-
537
)
180
Reynolds
I. J.
Hastings
T. G.
Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation
J. Neurosci.
1995
, vol. 
15
 (pg. 
3318
-
3327
)
181
Bolanos
J. P.
Almeida
A.
Fernandez
E.
Medina
J. M.
Land
J. M.
Clark
J. B.
Heales
S. J.
Potential mechanisms for nitric oxide-mediated impairment of brain mitochondrial energy metabolism
Biochem. Soc. Trans.
1997
, vol. 
25
 (pg. 
944
-
949
)
182
Perez-Severiano
F.
Rios
C.
Segovia
J.
Striatal oxidative damage parallels the expression of a neurological phenotype in mice transgenic for the mutation of Huntington's disease
Brain Res.
2000
, vol. 
862
 (pg. 
234
-
237
)
183
Halliwell
B.
Oxidative stress and neurodegeneration: where are we now?
J. Neurochem.
2006
, vol. 
97
 (pg. 
1634
-
1658
)
184
Stavrovskaya
I. G.
Kristal
B. S.
The powerhouse takes control of the cell: is the mitochondrial permeability transition a viable therapeutic target against neuronal dysfunction and death?
Free Radical Biol. Med.
2005
, vol. 
38
 (pg. 
687
-
697
)
185
Chang
D. T.
Rintoul
G. L.
Pandipati
S.
Reynolds
I. J.
Mutant huntingtin aggregates impair mitochondrial movement and trafficking in cortical neurons
Neurobiol. Dis.
2006
, vol. 
22
 (pg. 
388
-
400
)
186
Smeitink
J.
van den Heuvel
L.
DiMauro
S.
The genetics and pathology of oxidative phosphorylation
Nat. Rev. Genet.
2001
, vol. 
2
 (pg. 
342
-
352
)
187
Polidori
M. C.
Mecocci
P.
Browne
S. E.
Senin
U.
Beal
M. F.
Oxidative damage to mitochondrial DNA in Huntington's disease parietal cortex
Neurosci. Lett.
1999
, vol. 
272
 (pg. 
53
-
56
)
188
Bogdanov
M. B.
Andreassen
O. A.
Dedeoglu
A.
Ferrante
R. J.
Beal
M. F.
Increased oxidative damage to DNA in a transgenic mouse model of Huntington's disease
J. Neurochem.
2001
, vol. 
79
 (pg. 
1246
-
1249
)
189
Browne
S. E.
Bowling
A. C.
MacGarvey
U.
Baik
M. J.
Berger
S. C.
Muqit
M. M.
Bird
E. D.
Beal
M. F.
Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia
Ann. Neurol.
1997
, vol. 
41
 (pg. 
646
-
653
)
190
Taylor
R. W.
Turnbull
D. M.
Mitochondrial DNA mutations in human disease
Nat. Rev. Genet.
2005
, vol. 
6
 (pg. 
389
-
402
)
191
Liu
C. Y.
Lee
C. F.
Hong
C. H.
Wei
Y. H.
Mitochondrial DNA mutation and depletion increase the susceptibility of human cells to apoptosis
Ann. N.Y. Acad. Sci.
2004
, vol. 
1011
 (pg. 
133
-
145
)
192
Fraga
C. G.
Shigenaga
M. K.
Park
J. W.
Degan
P.
Ames
B. N.
Oxidative damage to DNA during aging: 8-hydroxy-2′-deoxyguanosine in rat organ DNA and urine
Proc. Natl. Acad. Sci. U.S.A.
1990
, vol. 
87
 (pg. 
4533
-
4537
)
193
Kovtun
I. V.
Liu
Y.
Bjoras
M.
Klungland
A.
Wilson
S. H.
McMurray
C. T.
OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells
Nature
2007
, vol. 
447
 (pg. 
447
-
452
)
194
Zourlidou
A.
Gidalevitz
T.
Kristiansen
M.
Landles
C.
Woodman
B.
Wells
D. J.
Latchman
D. S.
de Belleroche
J.
Tabrizi
S. J.
Morimoto
R. I.
Bates
G. P.
Hsp27 overexpression in the R6/2 mouse model of Huntington's disease: chronic neurodegeneration does not induce Hsp27 activation
Hum. Mol. Genet.
2007
, vol. 
16
 (pg. 
1078
-
1090
)
195
Perluigi
M.
Poon
H. F.
Maragos
W.
Pierce
W. M.
Klein
J. B.
Calabrese
V.
Cini
C.
De Marco
C.
Butterfield
D. A.
Proteomic analysis of protein expression and oxidative modification in r6/2 transgenic mice: a model of Huntington disease
Mol. Cell. Proteomics
2005
, vol. 
4
 (pg. 
1849
-
1861
)
196
Griffiths
H. R.
Moller
L.
Bartosz
G.
Bast
A.
Bertoni-Freddari
C.
Collins
A.
Cooke
M.
Coolen
S.
Haenen
G.
Hoberg
A. M.
, et al. 
Biomarkers
Mol. Aspects Med.
2002
, vol. 
23
 (pg. 
101
-
208
)
197
Poon
H. F.
Frasier
M.
Shreve
N.
Calabrese
V.
Wolozin
B.
Butterfield
D. A.
Mitochondrial associated metabolic proteins are selectively oxidized in A30P α-synuclein transgenic mice: a model of familial Parkinson's disease
Neurobiol. Dis.
2005
, vol. 
18
 (pg. 
492
-
498
)
198
Malorni
W.
Rainaldi
G.
Rivabene
R.
Santini
M. T.
Peterson
S. W.
Testa
U.
Donelli
G.
Cytoskeletal oxidative changes lead to alterations of specific cell surface receptors
Eur. J. Histochem.
1994
, vol. 
38
 
Suppl. 1
(pg. 
91
-
100
)
199
Bence
N. F.
Sampat
R. M.
Kopito
R. R.
Impairment of the ubiquitin–proteasome system by protein aggregation
Science
2001
, vol. 
292
 (pg. 
1552
-
1555
)
200
Jana
N. R.
Zemskov
E. A.
Wang
G.
Nukina
N.
Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release
Hum. Mol. Genet.
2001
, vol. 
10
 (pg. 
1049
-
1059
)
201
Ding
Q.
Lewis
J. J.
Strum
K. M.
Dimayuga
E.
Bruce-Keller
A. J.
Dunn
J. C.
Keller
J. N.
Polyglutamine expansion, protein aggregation, proteasome activity, and neural survival
J. Biol. Chem.
2002
, vol. 
277
 (pg. 
13935
-
13942
)
202
Bowman
A. B.
Yoo
S. Y.
Dantuma
N. P.
Zoghbi
H. Y.
Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin–proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation
Hum. Mol. Genet.
2005
, vol. 
14
 (pg. 
679
-
691
)
203
Diaz-Hernandez
M.
Hernandez
F.
Martin-Aparicio
E.
Gomez-Ramos
P.
Moran
M. A.
Castano
J. G.
Ferrer
I.
Avila
J.
Lucas
J. J.
Neuronal induction of the immunoproteasome in Huntington's disease
J. Neurosci.
2003
, vol. 
23
 (pg. 
11653
-
11661
)
204
Bett
J. S.
Goellner
G. M.
Woodman
B.
Pratt
G.
Rechsteiner
M.
Bates
G. P.
Proteasome impairment does not contribute to pathogenesis in R6/2 Huntington's disease mice: exclusion of proteasome activator REGγ as a therapeutic target
Hum. Mol. Genet.
2006
, vol. 
15
 (pg. 
33
-
44
)
205
Goldberg
A. L.
Protein degradation and protection against misfolded or damaged proteins
Nature
2003
, vol. 
426
 (pg. 
895
-
899
)
206
Ciechanover
A.
The ubiquitin proteolytic system: from a vague idea, through basic mechanisms, and onto human diseases and drug targeting
Neurology
2006
, vol. 
66
 (pg. 
S7
-
S19
)
207
DeMartino
G. N.
Slaughter
C. A.
The proteasome, a novel protease regulated by multiple mechanisms
J. Biol. Chem.
1999
, vol. 
274
 (pg. 
22123
-
22126
)
208
DeMartino
G. N.
Moomaw
C. R.
Zagnitko
O. P.
Proske
R. J.
Chu-Ping
M.
Afendis
S. J.
Swaffield
J. C.
Slaughter
C. A.
PA700, an ATP-dependent activator of the 20 S proteasome, is an ATPase containing multiple members of a nucleotide-binding protein family
J. Biol. Chem.
1994
, vol. 
269
 (pg. 
20878
-
20884
)
209
Hershko
A.
Ciechanover
A.
The ubiquitin system
Annu. Rev. Biochem.
1998
, vol. 
67
 (pg. 
425
-
479
)
210
Goldberg
A. L.
Cascio
P.
Saric
T.
Rock
K. L.
The importance of the proteasome and subsequent proteolytic steps in the generation of antigenic peptides
Mol. Immunol.
2002
, vol. 
39
 (pg. 
147
-
164
)
211
Madura
K.
Rad23 and Rpn10: perennial wallflowers join the melee
Trends Biochem. Sci.
2004
, vol. 
29
 (pg. 
637
-
640
)
212
Fruh
K.
Gossen
M.
Wang
K.
Bujard
H.
Peterson
P. A.
Yang
Y.
Displacement of housekeeping proteasome subunits by MHC-encoded LMPs: a newly discovered mechanism for modulating the multicatalytic proteinase complex
EMBO J.
1994
, vol. 
13
 (pg. 
3236
-
3244
)
213
Bingol
B.
Schuman
E. M.
Activity-dependent dynamics and sequestration of proteasomes in dendritic spines
Nature
2006
, vol. 
441
 (pg. 
1144
-
1148
)
214
Cummings
C. J.
Mancini
M. A.
Antalffy
B.
DeFranco
D. B.
Orr
H. T.
Zoghbi
H. Y.
Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1
Nat. Genet.
1998
, vol. 
19
 (pg. 
148
-
154
)
215
Bennett
E. J.
Bence
N. F.
Jayakumar
R.
Kopito
R. R.
Global impairment of the ubiquitin–proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation
Mol. Cell
2005
, vol. 
17
 (pg. 
351
-
365
)
216
Kim
S.
Nollen
E. A.
Kitagawa
K.
Bindokas
V. P.
Morimoto
R. I.
Polyglutamine protein aggregates are dynamic
Nat. Cell Biol.
2002
, vol. 
4
 (pg. 
826
-
831
)
217
Holmberg
C. I.
Staniszewski
K. E.
Mensah
K. N.
Matouschek
A.
Morimoto
R. I.
Inefficient degradation of truncated polyglutamine proteins by the proteasome
EMBO J.
2004
, vol. 
23
 (pg. 
4307
-
4318
)
218
Venkatraman
P.
Wetzel
R.
Tanaka
M.
Nukina
N.
Goldberg
A. L.
Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins
Mol. Cell
2004
, vol. 
14
 (pg. 
95
-
104
)
219
Diaz-Hernandez
M.
Valera
A. G.
Moran
M. A.
Gomez-Ramos
P.
Alvarez-Castelao
B.
Castano
J. G.
Hernandez
F.
Lucas
J. J.
Inhibition of 26S proteasome activity by huntingtin filaments but not inclusion bodies isolated from mouse and human brain
J. Neurochem.
2006
, vol. 
98
 (pg. 
1585
-
1596
)
220
Seo
H.
Sonntag
K. C.
Isacson
O.
Generalized brain and skin proteasome inhibition in Huntington's disease
Ann. Neurol.
2004
, vol. 
56
 (pg. 
319
-
328
)
221
Seo
H.
Sonntag
K. C.
Kim
W.
Cattaneo
E.
Isacson
O.
Proteasome activator enhances survival of huntington's disease neuronal model cells
PLoS ONE
2007
, vol. 
2
 pg. 
e238
 
222
Beister
A.
Kraus
P.
Kuhn
W.
Dose
M.
Weindl
A.
Gerlach
M.
The N-methyl-D-aspartate antagonist memantine retards progression of Huntington's disease
J. Neural Transm. Suppl.
2004
, vol. 
68
 (pg. 
117
-
122
)
223
Ravikumar
B.
Vacher
C.
Berger
Z.
Davies
J. E.
Luo
S.
Oroz
L. G.
Scaravilli
F.
Easton
D. F.
Duden
R.
O'Kane
C. J.
Rubinsztein
D. C.
Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease
Nat. Genet.
2004
, vol. 
36
 (pg. 
585
-
595
)
224
Tsai
Y. C.
Fishman
P. S.
Thakor
N. V.
Oyler
G. A.
Parkin facilitates the elimination of expanded polyglutamine proteins and leads to preservation of proteasome function
J. Biol. Chem.
2003
, vol. 
278
 (pg. 
22044
-
22055
)
225
Martin-Aparicio
E.
Yamamoto
A.
Hernandez
F.
Hen
R.
Avila
J.
Lucas
J. J.
Proteasomal-dependent aggregate reversal and absence of cell death in a conditional mouse model of Huntington's disease
J. Neurosci.
2001
, vol. 
21
 (pg. 
8772
-
8781
)
226
Waelter
S.
Boeddrich
A.
Lurz
R.
Scherzinger
E.
Lueder
G.
Lehrach
H.
Wanker
E. E.
Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation
Mol. Biol. Cell
2001
, vol. 
12
 (pg. 
1393
-
1407
)
227
Ravikumar
B.
Duden
R.
Rubinsztein
D. C.
Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy
Hum. Mol. Genet.
2002
, vol. 
11
 (pg. 
1107
-
1117
)
228
Bhutani
N.
Venkatraman
P.
Goldberg
A. L.
Puromycin-sensitive aminopeptidase is the major peptidase responsible for digesting polyglutamine sequences released by proteasomes during protein degradation
EMBO J.
2007
, vol. 
26
 (pg. 
1385
-
1396
)
229
Sanchez
I.
Mahlke
C.
Yuan
J.
Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders
Nature
2003
, vol. 
421
 (pg. 
373
-
379
)
230
Davies
J. E.
Sarkar
S.
Rubinsztein
D. C.
Trehalose reduces aggregate formation and delays pathology in a transgenic mouse model of oculopharyngeal muscular dystrophy
Hum. Mol. Genet.
2006
, vol. 
15
 (pg. 
23
-
31
)
231
Li
W.
Serpell
L. C.
Carter
W. J.
Rubinsztein
D. C.
Huntington
J. A.
Expression and characterization of full-length human huntingtin, an elongated HEAT repeat protein
J. Biol. Chem.
2006
, vol. 
281
 (pg. 
15916
-
15922
)
232
Cepeda
C.
Hurst
R. S.
Calvert
C. R.
Hernandez-Echeagaray
E.
Nguyen
O. K.
Jocoy
E.
Christian
L. J.
Ariano
M. A.
Levine
M. S.
Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington's disease
J. Neurosci.
2003
, vol. 
23
 (pg. 
961
-
969
)
233
Calabresi
P.
Centonze
D.
Pisani
A.
Sancesario
G.
Gubellini
P.
Marfia
G. A.
Bernardi
G.
Striatal spiny neurons and cholinergic interneurons express differential ionotropic glutamatergic responses and vulnerability: implications for ischemia and Huntington's disease
Ann. Neurol.
1998
, vol. 
43
 (pg. 
586
-
597
)
234
Kuppenbender
K. D.
Standaert
D. G.
Feuerstein
T. J.
Penney
J. B.
Jr
Young
A. B.
Landwehrmeyer
G. B.
Expression of NMDA receptor subunit mRNAs in neurochemically identified projection and interneurons in the human striatum
J. Comp. Neurol.
2000
, vol. 
419
 (pg. 
407
-
421
)
235
Maragakis
N. J.
Rothstein
J. D.
Glutamate transporters in neurologic disease
Arch. Neurol.
2001
, vol. 
58
 (pg. 
365
-
370
)
236
Lievens
J. C.
Woodman
B.
Mahal
A.
Spasic-Boscovic
O.
Samuel
D.
Kerkerian-Le Goff
L.
Bates
G. P.
Impaired glutamate uptake in the R6 Huntington's disease transgenic mice
Neurobiol. Dis.
2001
, vol. 
8
 (pg. 
807
-
821
)
237
Behrens
P. F.
Franz
P.
Woodman
B.
Lindenberg
K. S.
Landwehrmeyer
G. B.
Impaired glutamate transport and glutamate–glutamine cycling: downstream effects of the Huntington mutation
Brain
2002
, vol. 
125
 (pg. 
1908
-
1922
)
238
Popoli
P.
Blum
D.
Martire
A.
Ledent
C.
Ceruti
S.
Abbracchio
M. P.
Functions, dysfunctions and possible therapeutic relevance of adenosine A2A receptors in Huntington's disease
Prog. Neurobiol.
2007
, vol. 
81
 (pg. 
331
-
348
)
239
Shin
J. Y.
Fang
Z. H.
Yu
Z. X.
Wang
C. E.
Li
S. H.
Li
X. J.
Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity
J. Cell Biol.
2005
, vol. 
171
 (pg. 
1001
-
1012
)
240
Gu
X.
Li
C.
Wei
W.
Lo
V.
Gong
S.
Li
S. H.
Iwasato
T.
Itohara
S.
Li
X. J.
Mody
I.
, et al. 
Pathological cell–cell interactions elicited by a neuropathogenic form of mutant huntingtin contribute to cortical pathogenesis in HD mice
Neuron
2005
, vol. 
46
 (pg. 
433
-
444
)
241
Li
X. J.
Li
S. H.
Sharp
A. H.
Nucifora
F. C.
Jr
Schilling
G.
Lanahan
A.
Worley
P.
Snyder
S. H.
Ross
C. A.
A huntingtin-associated protein enriched in brain with implications for pathology
Nature
1995
, vol. 
378
 (pg. 
398
-
402
)
242
Kalchman
M. A.
Koide
H. B.
McCutcheon
K.
Graham
R. K.
Nichol
K.
Nishiyama
K.
Kazemi-Esfarjani
P.
Lynn
F. C.
Wellington
C.
Metzler
M.
, et al. 
HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane associated huntingtin in the brain
Nat. Genet.
1997
, vol. 
16
 (pg. 
44
-
53
)
243
Wanker
E. E.
Rovira
C.
Scherzinger
E.
Hasenbank
R.
Walter
S.
Tait
D.
Colicelli
J.
Lehrach
H.
HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system
Hum. Mol. Genet.
1997
, vol. 
6
 (pg. 
487
-
495
)
244
Boutell
J. M.
Wood
J. D.
Harper
P. S.
Jones
A. L.
Huntingtin interacts with cystathionine β-synthase
Hum. Mol. Genet.
1998
, vol. 
7
 (pg. 
371
-
378
)
245
Faber
P. W.
Barnes
G. T.
Srinidhi
J.
Chen
J.
Gusella
J. F.
MacDonald
M. E.
Huntingtin interacts with a family of WW domain proteins
Hum. Mol. Genet.
1998
, vol. 
7
 (pg. 
1463
-
1474
)
246
Holbert
S.
Dedeoglu
A.
Humbert
S.
Saudou
F.
Ferrante
R. J.
Neri
C.
Cdc42-interacting protein 4 binds to huntingtin: neuropathologic and biological evidence for a role in Huntington's disease
Proc. Natl. Acad. Sci. U.S.A.
2003
, vol. 
100
 (pg. 
2712
-
2717
)
247
Holbert
S.
Denghien
I.
Kiechle
T.
Rosenblatt
A.
Wellington
C.
Hayden
M. R.
Margolis
R. L.
Ross
C. A.
Dausset
J.
Ferrante
R. J.
Neri
C.
The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis
Proc. Natl. Acad. Sci. U.S.A.
2001
, vol. 
98
 (pg. 
1811
-
1816
)
248
Goehler
H.
Lalowski
M.
Stelzl
U.
Waelter
S.
Stroedicke
M.
Worm
U.
Droege
A.
Lindenberg
K. S.
Knoblich
M.
Haenig
C.
, et al. 
A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease
Mol. Cell
2004
, vol. 
15
 (pg. 
853
-
865
)
249
Kaltenbach
L. S.
Romero
E.
Becklin
R. R.
Chettier
R.
Bell
R.
Phansalkar
A.
Strand
A.
Torcassi
C.
Savage
J.
Hurlburt
A.
, et al. 
Huntingtin interacting proteins are genetic modifiers of neurodegeneration
PLoS Genet.
2007
, vol. 
3
 pg. 
e82
 
250
Heiser
V.
Engemann
S.
Brocker
W.
Dunkel
I.
Boeddrich
A.
Waelter
S.
Nordhoff
E.
Lurz
R.
Schugardt
N.
Rautenberg
S.
, et al. 
Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay
Proc. Natl. Acad. Sci. U.S.A.
2002
, vol. 
99
 
Suppl. 4
(pg. 
16400
-
16406
)
251
Coufal
M.
Maxwell
M. M.
Russel
D. E.
Amore
A. M.
Altmann
S. M.
Hollingsworth
Z. R.
Young
A. B.
Housman
D. E.
Kazantsev
A. G.
Discovery of a novel small-molecule targeting selective clearance of mutant huntingtin fragments
J. Biomol. Screen.
2007
, vol. 
12
 (pg. 
351
-
360
)
252
Yamamoto
A.
Cremona
M. L.
Rothman
J. E.
Autophagymediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway
J. Cell Biol.
2006
, vol. 
172
 (pg. 
719
-
731
)
253
Nollen
E. A.
Garcia
S. M.
van Haaften
G.
Kim
S.
Chavez
A.
Morimoto
R. I.
Plasterk
R. H.
Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation
Proc. Natl. Acad. Sci. U.S.A.
2004
, vol. 
101
 (pg. 
6403
-
6408
)
254
Aiken
C. T.
Tobin
A. J.
Schweitzer
E. S.
A cell-based screen for drugs to treat Huntington's disease
Neurobiol. Dis.
2004
, vol. 
16
 (pg. 
546
-
555
)
255
Piccioni
F.
Roman
B. R.
Fischbeck
K. H.
Taylor
J. P.
A screen for drugs that protect against the cytotoxicity of polyglutamine-expanded androgen receptor
Hum. Mol. Genet.
2004
, vol. 
13
 (pg. 
437
-
446
)
256
Giorgini
F.
Guidetti
P.
Nguyen
Q.
Bennett
S. C.
Muchowski
P. J.
A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease
Nat. Genet.
2005
, vol. 
37
 (pg. 
526
-
531
)
257
Willingham
S.
Outeiro
T. F.
DeVit
M. J.
Lindquist
S. L.
Muchowski
P. J.
Yeast genes that enhance the toxicity of a mutant huntingtin fragment or α-synuclein
Science
2003
, vol. 
302
 (pg. 
1769
-
1772
)
258
Faber
P. W.
Voisine
C.
King
D. C.
Bates
E. A.
Hart
A. C.
Glutamine/proline-rich PQE-1 proteins protect Caenorhabditis elegans neurons from huntingtin polyglutamine neurotoxicity
Proc. Natl. Acad. Sci. U.S.A.
2002
, vol. 
99
 (pg. 
17131
-
17136
)
259
Kazemi-Esfarjani
P.
Benzer
S.
Genetic suppression of polyglutamine toxicity in Drosophila
Science
2000
, vol. 
287
 (pg. 
1837
-
1840
)
260
Jackson
G. R.
Salecker
I.
Dong
X.
Yao
X.
Arnheim
N.
Faber
P. W.
MacDonald
M. E.
Zipursky
S. L.
Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons
Neuron
1998
, vol. 
21
 (pg. 
633
-
642
)
261
Warrick
J. M.
Chan
H. Y.
Gray-Board
G. L.
Chai
Y.
Paulson
H. L.
Bonini
N. M.
Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70
Nat. Genet.
1999
, vol. 
23
 (pg. 
425
-
428
)
262
Warrick
J. M.
Paulson
H. L.
Gray-Board
G. L.
Bui
Q. T.
Fischbeck
K. H.
Pittman
R. N.
Bonini
N. M.
Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila
Cell
1998
, vol. 
93
 (pg. 
939
-
949
)
263
Kazemi-Esfarjani
P.
Benzer
S.
Suppression of polyglutamine toxicity by a Drosophila homolog of myeloid leukemia factor 1
Hum. Mol. Genet.
2002
, vol. 
11
 (pg. 
2657
-
2672
)
264
Fernandez-Funez
P.
Nino-Rosales
M. L.
de Gouyon
B.
She
W. C.
Luchak
J. M.
Martinez
P.
Turiegano
E.
Benito
J.
Capovilla
M.
Skinner
P. J.
, et al. 
Identification of genes that modify ataxin-1-induced neurodegeneration
Nature
2000
, vol. 
408
 (pg. 
101
-
106
)
265
Bilen
J.
Liu
N.
Burnett
B. G.
Pittman
R. N.
Bonini
N. M.
MicroRNA pathways modulate polyglutamine-induced neurodegeneration
Mol. Cell
2006
, vol. 
24
 (pg. 
157
-
163
)
266
Thompson
J. C.
Snowden
J. S.
Craufurd
D.
Neary
D.
Behavior in Huntington's disease: dissociating cognition-based and mood-based changes
J. Neuropsychiatry Clin. Neurosci.
2002
, vol. 
14
 (pg. 
37
-
43
)
267
Folstein
S. E.
Chase
G. A.
Wahl
W. E.
McDonnell
A. M.
Folstein
M. F.
Huntington disease in Maryland: clinical aspects of racial variation
Am. J. Hum. Genet.
1987
, vol. 
41
 (pg. 
168
-
179
)
268
Baliko
L.
Csala
B.
Czopf
J.
Suicide in Hungarian Huntington's disease patients
Neuroepidemiology
2004
, vol. 
23
 (pg. 
258
-
260
)
269
Anderson
K. E.
Louis
E. D.
Stern
Y.
Marder
K. S.
Cognitive correlates of obsessive and compulsive symptoms in Huntington's disease
Am. J. Psychiatry
2001
, vol. 
158
 (pg. 
799
-
801
)
270
Bonelli
R. M.
Mirtazapine in suicidal Huntington's disease
Ann. Pharmacother.
2003
, vol. 
37
 pg. 
452
 
271
Patzold
T.
Brune
M.
Obsessive compulsive disorder in Huntington disease: a case of isolated obsessions successfully treated with sertraline
Neuropsychiatry Neuropsychol. Behav. Neurol.
2002
, vol. 
15
 (pg. 
216
-
219
)
272
Paleacu
D.
Anca
M.
Giladi
N.
Olanzapine in Huntington's disease
Acta Neurol. Scand.
2002
, vol. 
105
 (pg. 
441
-
444
)
273
Madhusoodanan
S.
Brenner
R.
Use of risperidone in psychosis associated with Huntington's disease
Am. J. Geriatr. Psychiatry
1998
, vol. 
6
 (pg. 
347
-
349
)
274
Saft
C.
Andrich
J.
Kraus
P. H.
Przuntek
H.
Amisulpride in Huntington's disease
Psychiatr. Prax.
2005
, vol. 
32
 (pg. 
363
-
366
)
275
Alpay
M.
Koroshetz
W. J.
Quetiapine in the treatment of behavioral disturbances in patients with Huntington's disease
Psychosomatics
2006
, vol. 
47
 (pg. 
70
-
72
)
276
Huntington Study Group
Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial
Neurology
2006
, vol. 
66
 (pg. 
366
-
372
)
277
van Vugt
J. P.
Siesling
S.
Vergeer
M.
van der Velde
E. A.
Roos
R. A.
Clozapine versus placebo in Huntington's disease: a double blind randomised comparative study
J. Neurol. Neurosurg. Psychiatry
1997
, vol. 
63
 (pg. 
35
-
39
)
278
Bonelli
R. M.
Mahnert
F. A.
Niederwieser
G.
Olanzapine for Huntington's disease: an open label study
Clin. Neuropharmacol.
2002
, vol. 
25
 (pg. 
263
-
265
)
279
de Tommaso
M.
Difruscolo
O.
Sciruicchio
V.
Specchio
N.
Livrea
P.
Two years' follow-up of rivastigmine treatment in Huntington disease
Clin. Neuropharmacol.
2007
, vol. 
30
 (pg. 
43
-
46
)
280
Cubo
E.
Shannon
K. M.
Tracy
D.
Jaglin
J. A.
Bernard
B. A.
Wuu
J.
Leurgans
S. E.
Effect of donepezil on motor and cognitive function in Huntington disease
Neurology
2006
, vol. 
67
 (pg. 
1268
-
1271
)
281
Wang
Y. L.
Liu
W.
Wada
E.
Murata
M.
Wada
K.
Kanazawa
I.
Clinico-pathological rescue of a model mouse of Huntington's disease by siRNA
Neurosci. Res.
2005
, vol. 
53
 (pg. 
241
-
249
)
282
Xia
H.
Mao
Q.
Eliason
S. L.
Harper
S. Q.
Martins
I. H.
Orr
H. T.
Paulson
H. L.
Yang
L.
Kotin
R. M.
Davidson
B. L.
RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia
Nat. Med.
2004
, vol. 
10
 (pg. 
816
-
820
)
283
Miller
V. M.
Xia
H.
Marrs
G. L.
Gouvion
C. M.
Lee
G.
Davidson
B. L.
Paulson
H. L.
Allele-specific silencing of dominant disease genes
Proc. Natl. Acad. Sci. U.S.A.
2003
, vol. 
100
 (pg. 
7195
-
7200
)
284
Berger
Z.
Ravikumar
B.
Menzies
F. M.
Oroz
L. G.
Underwood
B. R.
Pangalos
M. N.
Schmitt
I.
Wullner
U.
Evert
B. O.
O'Kane
C. J.
Rubinsztein
D. C.
Rapamycin alleviates toxicity of different aggregate-prone proteins
Hum. Mol. Genet.
2006
, vol. 
15
 (pg. 
433
-
442
)
285
Sanchez
I.
Xu
C. J.
Juo
P.
Kakizaka
A.
Blenis
J.
Yuan
J.
Caspase-8 is required for cell death induced by expanded polyglutamine repeats
Neuron
1999
, vol. 
22
 (pg. 
623
-
633
)
286
Wang
X.
Zhu
S.
Drozda
M.
Zhang
W.
Stavrovskaya
I. G.
Cattaneo
E.
Ferrante
R. J.
Kristal
B. S.
Friedlander
R. M.
Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington's disease
Proc. Natl. Acad. Sci. U.S.A.
2003
, vol. 
100
 (pg. 
10483
-
10487
)
287
Smith
D. L.
Woodman
B.
Mahal
A.
Sathasivam
K.
Ghazi-Noori
S.
Lowden
P. A.
Bates
G. P.
Hockly
E.
Minocycline and doxycycline are not beneficial in a model of Huntington's disease
Ann. Neurol.
2003
, vol. 
54
 (pg. 
186
-
196
)
288
Bonelli
R. M.
Hodl
A. K.
Hofmann
P.
Kapfhammer
H. P.
Neuroprotection in Huntington's disease: a 2-year study on minocycline
Int. Clin. Psychopharmacol.
2004
, vol. 
19
 (pg. 
337
-
342
)
289
Thomas
M.
Ashizawa
T.
Jankovic
J.
Minocycline in Huntington's disease: a pilot study
Mov. Disord.
2004
, vol. 
19
 (pg. 
692
-
695
)
290
Varma
H.
Cheng
R.
Voisine
C.
Hart
A. C.
Stockwell
B. R.
Inhibitors of metabolism rescue cell death in Huntington's disease models
Proc. Natl. Acad. Sci. U.S.A.
2007
, vol. 
104
 (pg. 
14525
-
14530
)
291
Ferrante
R. J.
Andreassen
O. A.
Jenkins
B. G.
Dedeoglu
A.
Kuemmerle
S.
Kubilus
J. K.
Kaddurah-Daouk
R.
Hersch
S. M.
Beal
M. F.
Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease
J. Neurosci.
2000
, vol. 
20
 (pg. 
4389
-
4397
)
292
Dedeoglu
A.
Kubilus
J. K.
Jeitner
T. M.
Matson
S. A.
Bogdanov
M.
Kowall
N. W.
Matson
W. R.
Cooper
A. J.
Ratan
R. R.
Beal
M. F.
, et al. 
Therapeutic effects of cystamine in a murine model of Huntington's disease
J. Neurosci.
2002
, vol. 
22
 (pg. 
8942
-
8950
)
293
Dubinsky
R.
Gray
C.
CYTE-I-HD: phase I dose finding and tolerability study of cysteamine (Cystagon) in Huntington's disease
Mov. Disord.
2006
, vol. 
21
 (pg. 
530
-
533
)
294
Sittler
A.
Lurz
R.
Lueder
G.
Priller
J.
Lehrach
H.
Hayer-Hartl
M. K.
Hartl
F. U.
Wanker
E. E.
Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease
Hum. Mol. Genet.
2001
, vol. 
10
 (pg. 
1307
-
1315
)
295
Tanaka
M.
Machida
Y.
Niu
S.
Ikeda
T.
Jana
N. R.
Doi
H.
Kurosawa
M.
Nekooki
M.
Nukina
N.
Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease
Nat. Med.
2004
, vol. 
10
 (pg. 
148
-
154
)
296
Burlina
A. B.
Ogier
H.
Korall
H.
Trefz
F. K.
Long-term treatment with sodium phenylbutyrate in ornithine transcarbamylase-deficient patients
Mol. Genet. Metab.
2001
, vol. 
72
 (pg. 
351
-
355
)
297
Schiefer
J.
Landwehrmeyer
G. B.
Luesse
H. G.
Sprunken
A.
Puls
C.
Milkereit
A.
Milkereit
E.
Kosinski
C. M.
Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington's disease
Mov. Disord.
2002
, vol. 
17
 (pg. 
748
-
757
)
298
Ferrante
R. J.
Andreassen
O. A.
Dedeoglu
A.
Ferrante
K. L.
Jenkins
B. G.
Hersch
S. M.
Beal
M. F.
Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease
J. Neurosci.
2002
, vol. 
22
 (pg. 
1592
-
1599
)
299
O'Suilleabhain
P.
Dewey
R. B.
Jr
A randomized trial of amantadine in Huntington disease
Arch. Neurol.
2003
, vol. 
60
 (pg. 
996
-
998
)
300
Huntington Study Group
Dosage effects of riluzole in Huntington's disease: a multicenter placebo-controlled study
Neurology
2003
, vol. 
61
 (pg. 
1551
-
1556
)
301
Kremer
B.
Clark
C. M.
Almqvist
E. W.
Raymond
L. A.
Graf
P.
Jacova
C.
Mezei
M.
Hardy
M. A.
Snow
B.
Martin
W.
Hayden
M. R.
Influence of lamotrigine on progression of early Huntington disease: a randomized clinical trial
Neurology
1999
, vol. 
53
 (pg. 
1000
-
1011
)
302
Huntington Study Group
A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease
Neurology
2001
, vol. 
57
 (pg. 
397
-
404
)
303
Dunnett
S. B.
Carter
R. J.
Watts
C.
Torres
E. M.
Mahal
A.
Mangiarini
L.
Bates
G.
Morton
A. J.
Striatal transplantation in a transgenic mouse model of Huntington's disease
Exp. Neurol.
1998
, vol. 
154
 (pg. 
31
-
40
)
304
van Dellen
A.
Deacon
R.
York
D.
Blakemore
C.
Hannan
A. J.
Anterior cingulate cortical transplantation in transgenic Huntington's disease mice
Brain Res. Bull.
2001
, vol. 
56
 (pg. 
313
-
318
)
305
Sramka
M.
Rattaj
M.
Molina
H.
Vojtassak
J.
Belan
V.
Ruzicky
E.
Stereotactic technique and pathophysiological mechanisms of neurotransplantation in Huntington's chorea
Stereotact. Funct. Neurosurg.
1992
, vol. 
58
 (pg. 
79
-
83
)
306
Madrazo
I.
Franco-Bourland
R. E.
Castrejon
H.
Cuevas
C.
Ostrosky-Solis
F.
Fetal striatal homotransplantation for Huntington's disease: first two case reports
Neurol. Res.
1995
, vol. 
17
 (pg. 
312
-
315
)
307
Kopyov
O. V.
Jacques
S.
Lieberman
A.
Duma
C. M.
Eagle
K. S.
Safety of intrastriatal neurotransplantation for Huntington's disease patients
Exp. Neurol.
1998
, vol. 
149
 (pg. 
97
-
108
)
308
Bachoud-Levi
A.
Bourdet
C.
Brugieres
P.
Nguyen
J. P.
Grandmougin
T.
Haddad
B.
Jeny
R.
Bartolomeo
P.
Boisse
M. F.
Barba
G. D.
, et al. 
Safety and tolerability assessment of intrastriatal neural allografts in five patients with Huntington's disease
Exp. Neurol.
2000
, vol. 
161
 (pg. 
194
-
202
)
309
Rosser
A. E.
Barker
R. A.
Harrower
T.
Watts
C.
Farrington
M.
Ho
A. K.
Burnstein
R. M.
Menon
D. K.
Gillard
J. H.
Pickard
J.
Dunnett
S. B.
Unilateral transplantation of human primary fetal tissue in four patients with Huntington's disease: NEST-UK safety report ISRCTN no. 36485475
J. Neurol. Neurosurg. Psychiatry
2002
, vol. 
73
 (pg. 
678
-
685
)
310
Schumacher
J. M.
Ellias
S. A.
Palmer
E. P.
Kott
H. S.
Dinsmore
J.
Dempsey
P. K.
Fischman
A. J.
Thomas
C.
Feldman
R. G.
Kassissieh
S.
, et al. 
Transplantation of embryonic porcine mesencephalic tissue in patients with PD
Neurology
2000
, vol. 
54
 (pg. 
1042
-
1050
)
311
Hauser
R. A.
Furtado
S.
Cimino
C. R.
Delgado
H.
Eichler
S.
Schwartz
S.
Scott
D.
Nauert
G. M.
Soety
E.
Sossi
V.
, et al. 
Bilateral human fetal striatal transplantation in Huntington's disease
Neurology
2002
, vol. 
58
 (pg. 
687
-
695
)
312
Gaura
V.
Bachoud-Levi
A. C.
Ribeiro
M. J.
Nguyen
J. P.
Frouin
V.
Baudic
S.
Brugieres
P.
Mangin
J. F.
Boisse
M. F.
Palfi
S.
, et al. 
Striatal neural grafting improves cortical metabolism in Huntington's disease patients
Brain
2004
, vol. 
127
 (pg. 
65
-
72
)
313
Freeman
T. B.
Cicchetti
F.
Hauser
R. A.
Deacon
T. W.
Li
X. J.
Hersch
S. M.
Nauert
G. M.
Sanberg
P. R.
Kordower
J. H.
Saporta
S.
Isacson
O.
Transplanted fetal striatum in Huntington's disease: phenotypic development and lack of pathology
Proc. Natl. Acad. Sci. U.S.A.
2000
, vol. 
97
 (pg. 
13877
-
13882
)
314
Haque
N. S.
Isacson
O.
Neurotrophic factors NGF and FGF-2 alter levels of huntingtin (IT15) in striatal neuronal cell cultures
Cell Transplant.
2000
, vol. 
9
 (pg. 
623
-
627
)
315
Mittoux
V.
Joseph
J. M.
Conde
F.
Palfi
S.
Dautry
C.
Poyot
T.
Bloch
J.
Deglon
N.
Ouary
S.
Nimchinsky
E. A.
, et al. 
Restoration of cognitive and motor functions by ciliary neurotrophic factor in a primate model of Huntington's disease
Hum. Gene Ther.
2000
, vol. 
11
 (pg. 
1177
-
1187
)
316
Bloch
J.
Bachoud-Levi
A. C.
Deglon
N.
Lefaucheur
J. P.
Winkel
L.
Palfi
S.
Nguyen
J. P.
Bourdet
C.
Gaura
V.
Remy
P.
, et al. 
Neuroprotective gene therapy for Huntington's disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a phase I study
Hum. Gene Ther.
2004
, vol. 
15
 (pg. 
968
-
975
)
317
Underwood
B. R.
Broadhurst
D.
Dunn
W. B.
Ellis
D. I.
Michell
A. W.
Vacher
C.
Mosedale
D. E.
Kell
D. B.
Barker
R. A.
Grainger
D. J.
Rubinsztein
D. C.
Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles
Brain
2006
, vol. 
129
 (pg. 
877
-
886
)