Many of the major neurodegenerative disorders are characterized by the accumulation of intracellular protein aggregates in neurons and other cells in brain, suggesting that errors in protein quality control mechanisms associated with the aging process play a critical role in the onset and progression of disease. The increased understanding of the unfolded protein response (UPR) signaling network and, more specifically, the structure and function of eIF2α phosphatases has enabled the development or discovery of small molecule inhibitors that show great promise in restoring protein homeostasis and ameliorating neuronal damage and death. While this review focuses attention on one or more eIF2α phosphatases, the wide range of UPR proteins that are currently being explored as potential drug targets bodes well for the successful future development of therapies to preserve neuronal function and treat neurodegenerative disease.

Introduction

With the greater access to healthcare, many countries have seen sharp increases in the lifespan of their populations. This in turn has contributed to a rising global incidence in aging-related diseases, including many neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS or more commonly known as Lou Gehrig's disease) and Huntington's disease (HD) and the rare prion disease. Most concerning is that this trend shows little sign of abating. All the aforementioned diseases share a common characteristic, namely that the neurons in the affected regions of the brain accumulate intracellular aggregates of misfolded proteins, described as plaques, tangles and Lewy bodies. While the precise role of protein aggregation in the disease process continues to be a source of active debate, the presence of aggregated proteins and damaged mitochondria correlates with neuronal death. Protein synthesis places a high demand on the cell's energy stores. Thus, the cell's ability to synthesize and fold proteins is closely linked to the functional integrity of its mitochondria, such that aberrant protein homeostasis and damaged mitochondria are common to many neurodegenerative disorders. Interestingly, the familial or inherited forms of these diseases, while representing a small fraction of the diseased population, have been linked to mutations in genes that directly or indirectly affect protein quality control. Moreover, proteotoxicity resulting from aging-related disturbances in the unfolded protein response (UPR) plays a critical role in neurodegeneration [14]. This has focused attention on the UPR signaling pathways that are activated following the accumulation of misfolded proteins in the endoplasmic reticulum (ER) with the notion that pharmacological modulation of these pathways may yield novel treatments for neurodegenerative disease.

UPR, aging and neurodegeneration

The UPR is mediated by three ER-localized transmembrane proteins, which sense the accumulation of misfolded proteins in the lumen of the ER [5]. PERK and IRE1, which function as protein kinases, and ATF6, which is proteolytically processed in the Golgi apparatus to generate an active transcription factor, together orchestrate a complex transcriptional and translational program that limits and/or clears the cellular burden of misfolded proteins. In a simplified view of the UPR (Figure 1), ATF6 and Xbp1, the transcription factor whose expression is activated by IRE1, elevate the expression of numerous chaperones. IRE1 also enhances the proteasomal degradation of misfolded proteins, a process known as ER-associated protein degradation or ERAD. Thus, IRE1 and ATF6 activation increases the cell's tolerance for misfolded proteins. Indeed, the prior activation of these adaptive pathways preconditions cells, enabling them to survive subsequent bouts of protein misfolding. In contrast, PERK phosphorylates the eukaryotic initiation factor, eIF2α, to attenuate general protein synthesis, temporarily alleviating the burden on the cell's protein quality control machinery. Phosphorylation of eIF2α also enhances the translation of mRNAs encoding stress response proteins that facilitate the resolution of stress induced by misfolded proteins. Deficits in eIF2α phosphorylation resulting from imbalances in cellular eIF2α kinases and phosphatases, alterations in chaperone and co-chaperone expression and shifts in the protein clearance mechanisms, specifically the change in focus from proteasome to autophagosome, have all been associated with the process of aging [6]. Thus, protein misfolding not only escalates with age but also contributes to aging. Conversely, studies using genetically tractable model organisms argue that adaptation to environmental stress or resistance to proteotoxicity can extend lifespan [7].

The unfolded protein response.

Figure 1.
The unfolded protein response.

The schematic shows a simplified view of the UPR, which is mediated by three transmembrane sensors, IR1, ATF6 and PERK, located in the ER and senses the accumulation of misfolded proteins in the ER lumen. Upon the detection of misfolded proteins, IRE1 and PERK homodimerize and are activated by transphosphorylation. ATF6 is transported to the Golgi in response to ER stress, where it is proteolytically cleaved into an active transcription factor. IRE1 is the major activator of ERAD. ATF6 promotes the expression of numerous chaperones. Taken together, the two pathways provide for cellular adaptation or enhance the cell's ability to better cope with ER stress. In contrast, PERK, via the phosphorylation of eIF2α, controls global mRNA translation, resulting in the extensive remodeling of the cellular proteome, and is a key determinant of cell viability. Two cellular phosphatase complexes, consisting of GADD34/PP1 and CReP/PP1, reverse eIF2α phosphorylation and, thus, may also determine the cell's decision to live or die.

Figure 1.
The unfolded protein response.

The schematic shows a simplified view of the UPR, which is mediated by three transmembrane sensors, IR1, ATF6 and PERK, located in the ER and senses the accumulation of misfolded proteins in the ER lumen. Upon the detection of misfolded proteins, IRE1 and PERK homodimerize and are activated by transphosphorylation. ATF6 is transported to the Golgi in response to ER stress, where it is proteolytically cleaved into an active transcription factor. IRE1 is the major activator of ERAD. ATF6 promotes the expression of numerous chaperones. Taken together, the two pathways provide for cellular adaptation or enhance the cell's ability to better cope with ER stress. In contrast, PERK, via the phosphorylation of eIF2α, controls global mRNA translation, resulting in the extensive remodeling of the cellular proteome, and is a key determinant of cell viability. Two cellular phosphatase complexes, consisting of GADD34/PP1 and CReP/PP1, reverse eIF2α phosphorylation and, thus, may also determine the cell's decision to live or die.

An intriguing aspect of many neurodegenerative disorders, such as AD, PD, ALS and HD, is that even though they arise from mutations in different genes that then express folding-deficient proteins [812], the neuropathologies associated with these diseases share many similarities. For example, in addition to aggregation of the mutated proteins, intracellular aggregates containing phosphorylated-tau and TDP-43 are seen in postmortem samples from AD, PD, ALS and HD patients. Moreover, these aggregates accumulate over many decades, pointing to the contribution of aging-related deterioration of protein quality control mechanisms, and precede the onset of clinical symptoms or overt disease, suggesting a cause-and-effect relationship. Finally, numerous studies show that protein aggregates that occur in the above diseases act in a prion-like manner to transmit ER stress and promote death in neighboring cells, contributing to the spread of neuronal damage across many brain regions [13]. These observations have fostered the view that ER stress caused by aberrant accumulation of misfolded proteins in the ER lumen plays a key role in many neurodegenerative diseases. As the protein quality control mechanisms place high demands on the cell's energy reserves, ER stress and mitochondrial dysfunction are intricately intertwined and both probably contribute to cell death and disease [14,15]. Thus, another strategy being actively investigated is the pharmacological modulation of mitochondrial quality control, which may provide additional therapeutic options for neurodegenerative disease [16,17].

Even though the differing phenotypes that result from the disruptions of individual UPR genes in mice have highlighted a remarkable heterogeneity in the UPR signaling network in different tissues [18], this has not deterred researchers from searching for small molecules that target a wide range of UPR components to restore protein homeostasis in many cellular and animal models of neurodegenerative disease [1921]. This group effort will undoubtedly increase the likelihood of delivering drugs to treat various neurodegenerative disorders and, hopefully, offer the clinicians a toolbox of therapeutics to tailor the most effective or personalized treatments for individual patients.

Modulating eIF2α phosphorylation–dephosphorylation in mammals

Accumulating evidence points to the prolonged suppression of protein synthesis, mediated by the persistent activation of the PERK/P-eIF2α signaling pathway, playing a major role in determining cell fate or the cell's decision to live or die, when facing chronic ER stress. In neurons, translational control mediated by eIF2α phosphorylation also controls synaptic plasticity and memory formation [22]. Thus, not surprisingly, loss-of-function mutations in the human PERK gene result in the Wolcott–Rallison syndrome, with early postnatal diabetes, severe mental retardation and other developmental abnormalities [23]. These features are remarkably replicated in mice following the deletion of the mouse PERK gene. These animals also show significant prenatal lethality [24]. Thus, small molecule inhibitors of PERK, like GSK2606414, while reducing memory loss and behavioral deficits in the prion mouse model [25], also elevate blood sugar levels, highlighting deficits in β-cell function or early hallmarks of diabetes. However, PERK represents only one of the four mammalian eIF2α kinases that phosphorylate eIF2α on serine-51. Thus, substituting alanine in place of serine-51 in the mouse eIF2α gene not only ablates eIF2α phosphorylation, but also results in severe hypoglycemia and early postnatal death [26]. Analyzing the changes in gene expression that account for pancreatic toxicity, recent studies show a significant up-regulation of the type 1 interferon receptor (IFNAR1) in the pancreas, following the loss of function of PERK, and highlight a critical role for IFNAR1 in the ensuing apoptosis in the pancreatic islets [27]. This raises hopes for strategies that combine PERK inhibitors with drugs that can attenuate interferon signaling to yield safer treatments for human neurodegenerative disease, alleviating or eliminating the potential pancreatic damage. Interestingly, ISRIB, a small molecule, inhibits the stress response downstream from eIF2α kinases by an as-yet-unknown mechanism, restoring mRNA translation. Thus, ISRIB essentially makes cells resistant to the effects of P-eIF2α [28]. ISRIB offers an exciting new approach for attenuating ER stress without incurring the pancreatic toxicity observed with PERK inhibitors [29].

The alternative approach, targeting eIF2α phosphatases, also suggests that the pharmacological inhibition of these enzymes can be cytoprotective in several models of protein misfolding disorders [30]. Mammalian cells contain two eIF2α phosphatases that differ in the nature of their regulatory subunits, containing either PPP1R15A (also known as GADD34 or growth arrest and DNA damage-inducible transcript 34) or PPP1R15B (or CReP, constitutive repressor of eIF2α phosphorylation) associated with the catalytic subunit of protein phosphatase-1 (PP1). Deletion of both mouse PPP1R15A and PP1R15B genes yields no viable embryos [31]. However, when introduced into the eIF2α (S51A) background, which mimics the restoration of the eIF2α phosphatases, viable pups are born but fail to thrive after birth. These data highlight that eIF2α may be the primary if not sole target of PPP1R15A/B phosphatases but also emphasize that the ability to both phosphorylate and dephosphorylate eIF2α is vital for mouse development. Thus, eIF2α phosphorylation functions as a ‘rheostat’ to control protein homeostasis such that too much or too little of P-eIF2α compromises cell viability. It is noteworthy that PP1R15B/CReP is readily observed in healthy unstressed cells, whereas PPP1R15A/GADD34 is commonly detected only in stressed or diseased cells. Combining this observation with the finding that mice lacking a functional GADD34 gene are overtly normal, albeit responding less effectively to some metabolic stresses, and the CReP null mice are severely runted and die soon after birth [31] has prompted the argument that the pharmacological inhibition of GADD34, and not CReP, will yield safer therapies for protein misfolding disorders. This viewpoint was further crystallized following the recent identification of a mutation in the human PPP1R15B/CreP gene [32,33], which is associated with diabetes as well as developmental and functional deficits in the brain, a phenotype remarkably similar to Wolcott–Rallison syndrome. This emphasizes that drugs that target the GADD34-containing eIF2α phosphatase, if they are to be useful in the treatment of human disease, should also aim to restore the balance between eIF2α kinase(s) and phosphatase and to re-establish protein homeostasis.

Cellular functions of GADD34-containing eIF2α phosphatase

Biochemical and structural studies show that GADD34 derives its remarkable specificity as an eIF2α phosphatase by scaffolding eIF2α and PP1 [34]. The eIF2α phosphatase inhibitors, Salubrinal [35] and Guanabenz [36], are thought to mediate their inhibitory effects by disrupting the GADD34/PP1 complex. However, this mode of action remains controversial. Regardless, both compounds elevate eIF2α phosphorylation and demonstrate beneficial effects in a variety of cellular and animal models of neurodegenerative disease (discussed below). Guanabenz (also known as Wytensin) represents a particularly interesting starting point for drug development, as for over four decades, this FDA-approved blood pressure-lowering drug has shown excellent tolerability in humans. Being a ‘centrally-acting’ drug, primarily targeting the α-adrenergic receptor in the brain, with GADD34 being a secondary or off-target, Guanabenz's ability to cross the blood–brain barrier makes it a particularly interesting template for designing GADD34 inhibitors to treat neurological disease. However, structural studies of the GADD34/PP1 complex [34] have failed to identify the Guanabenz-binding site, precluding the pursuit of structural-based drug design, and more empirical medicinal chemistry approaches, known as iterative analoguing or ‘parachuting’, similar to that which yielded Sephin 1 [37], are being widely pursued. By comparison, Salubrinal targets both GADD34- and CReP-containing eIF2α phosphatases and displays poor solubility, making it a more challenging chemical scaffold to drive drug development.

Our recent studies show that the GADD34 mRNA is present and actively translated in unstressed cells, even though the protein product is essentially undetectable using currently available anti-GADD34 antibodies [38]. Moreover, ribosome foot-printing in cells that lack a functional GADD34 gene established that, in healthy unstressed cells, GADD34 regulates the translation of several hundred mRNAs, some encoding proteins implicated in various human diseases. This prompts a reappraisal of the widely held view, based largely on the lack of detection of the GADD34 protein in unstressed cells, that GADD34 inhibitors will have no detrimental effect on healthy cells. The GADD34 mRNA is among the earliest and most robustly translated following ER stress [39]. This early, nearly 30-fold elevation of the GADD34 protein, while still barely detectable, plays a crucial role in the recovery from transient inhibition of the translation of ER-targeted mRNAs, encoding the secretome, following ER stress. Most importantly, this low level of GADD34 is critical for the expression of many UPR proteins, including ATF4, CHOP, Xbp1, Bip and others. Thus, genetic or pharmacological inhibition of GADD34, which functions as a UPR ‘accelerator’ at this early stage, slows or delays the UPR (Figure 2), including the ER stress-mediated transcription of the GADD34 gene [38]. Another surprising finding was that, in the absence of GADD34 function, CReP gene transcription is activated by ER stress, albeit at later stages of the UPR. So, CReP may compensate for the loss of GADD34 to dephosphorylate P-eIF2α and restore the expression of ATF4 and CHOP and the downstream UPR. In normal wild-type cells, ATF4 and CHOP activate GADD34 gene transcription, resulting in readily detectable levels of the GADD34 protein. At these higher levels, GADD34 functions in a feedback manner as a UPR ‘brake’ to dephosphorylate P-eIF2α and restore general protein synthesis. If the ER stress is successfully resolved, the GADD34 protein is rapidly degraded by the proteasome [40] to the low or undetectable levels seen in unstressed cells. These data highlight a paradoxical role for GADD34, both as an accelerator and a brake for the UPR (Figure 2), and it is currently unclear whether and to what extent the impairment of these GADD34 functions is necessary to elicit the beneficial or deleterious effects of GADD34 inhibitors reported in various experimental models of neurodegenerative disease.

Revised view of PERK/P-eIF2α signaling.

Figure 2.
Revised view of PERK/P-eIF2α signaling.

The major outcome resulting from the stress of misfolded proteins, which activates PERK and results in eIF2α phosphorylation, is the repression of global mRNA translation. Simultaneously, P-eIF2α promotes the rapid translation of existing GADD34 mRNA. This generates low levels of GADD34 protein that function as an UPR ‘accelerator’ to facilitate a ‘second’ wave of translation, which includes the ATF4 mRNA, which then leads to transcription of the ATF4 target gene, CHOP. The two nuclear proteins, ATF4 and CHOP, have both been implicated in promoting transcription of the GADD34 gene, which dramatically elevates cellular GADD34 protein levels. The higher levels of GADD34 function in a feedback loop to dephosphorylate P-eIF2α, functioning as a UPR brake to counteract PERK signaling and restore general protein synthesis or cell recovery from translational repression. While small molecule ‘GADD34 inhibitors’, Guanabenz and Salubrinal, delay UPR progression at early stages [38], chronic exposure to these compounds may impair the ‘brake’ on eIF2α phosphorylation and promote UPR signaling.

Figure 2.
Revised view of PERK/P-eIF2α signaling.

The major outcome resulting from the stress of misfolded proteins, which activates PERK and results in eIF2α phosphorylation, is the repression of global mRNA translation. Simultaneously, P-eIF2α promotes the rapid translation of existing GADD34 mRNA. This generates low levels of GADD34 protein that function as an UPR ‘accelerator’ to facilitate a ‘second’ wave of translation, which includes the ATF4 mRNA, which then leads to transcription of the ATF4 target gene, CHOP. The two nuclear proteins, ATF4 and CHOP, have both been implicated in promoting transcription of the GADD34 gene, which dramatically elevates cellular GADD34 protein levels. The higher levels of GADD34 function in a feedback loop to dephosphorylate P-eIF2α, functioning as a UPR brake to counteract PERK signaling and restore general protein synthesis or cell recovery from translational repression. While small molecule ‘GADD34 inhibitors’, Guanabenz and Salubrinal, delay UPR progression at early stages [38], chronic exposure to these compounds may impair the ‘brake’ on eIF2α phosphorylation and promote UPR signaling.

Efficacy of eIF2α modulation in preclinical models of neurodegenerative diseases

Alzheimer's disease

AD is the most common form of dementia and is characterized by the progressive impairment of memory and other cognitive functions. The pathological features of AD include amyloid plaques and neurofibrillary tangles containing hyperphosphorylated-tau [41]. Amyloid plaques arise from the oligomerization of β-amyloid peptides following the proteolytic cleavage of the amyloid precursor protein (APP).

Aberrant activation of eIF2α kinases and P-eIF2α signaling has been consistently observed in the postmortem brains from sporadic AD patients as well as in mouse models of AD and the normal aging mouse brain [4246]. Moreover, the genetic suppression of PERK or GCN2 functions alleviates AD-related plasticity and memory deficits, particularly the hippocampal-dependent fear conditioning [47,48]. Haploinsufficiency of PERK in 5XFAD transgenic mice carrying familial AD-related mutant forms of APP and Presenilin 1 reduces BACE1 (β-site APP cleaving enzyme 1), responsible for Aβ peptide production, as well as ATF4 to promote the survival of cholinergic neurons [48]. This is particularly interesting as recent work shows that ATF4 is locally translated in axons exposed to Aβ peptide and undergoes retrograde transport to the soma to initiate gene transcription. This mechanism appears to determine the spread of neurodegenerative signals across the brain [49]. Enhanced GADD34 expression has been reported in neurons and oligodendrocytes from AD patients, leading to the suggestion that inhibiting GADD34 function may also moderate ER stress and promote neuroprotection in some AD models [50].

Salubrinal significantly attenuates Aβ-mediated neuronal toxicity in SK-N-SH human cholinergic neuroblastoma cells following the induction of BiP, an ER luminal chaperone, pivotal to the activation of ER stress [51]. Salubrinal also provides neuroprotection against Aβ-mediated neurotoxicity by inhibiting nuclear factor-kappa B (NF-κB) signaling [52], activated by Aβ in both neurons and microglial cells [53]. However, treatment of mice carrying conditional deletion of PERK with Sal003, a soluble Salubrinal analog, does not rescue Aβ-induced deficits in long-term potentiation or LTP [47]. Nonetheless, a recent study demonstrates that hippocampal-based object–place learning relies on P-eIF2α-mediated activation of group 1 metabotropic glutamate receptor (mGluR)-induced long-term depression [54], such that mice deficient in P-eIF2α-mediated mRNA translation fail to learn specific behavioral tasks. This suggests that pharmacological inhibition of eIF2α phosphatases should be examined in the appropriate AD models where alterations in mGluR-dependent synaptic depression have been implicated in AD development [55].

Parkinson's disease

PD is the second most common neurodegenerative disorder after AD, affecting ∼1% of the elderly population. While the majority of PD cases are sporadic, a small fraction (5–8%) is familial [56]. Clinical manifestations of PD, namely tremor, muscle rigidity, bradykinesia and postural instability, result from the loss of dopaminergic neurons in the substantia nigra pars compacta that also contain protein aggregates, termed Lewy bodies, with α-Synuclein as a major component [57].

While many mechanisms such as oxidative stress, mitochondrial dysfunction, defective ubiquitin proteasome system and autophagy have been implicated in the development of PD [58], recent studies using neurons derived from Parkinson patient-derived pluripotent stem cells point to ER stress as one of the earliest pathological events [59]. Emphasizing the role of ER stress in PD pathogenesis, histological evidence for the activation of the PERK pathway, namely P-PERK and P-eIF2α, is seen in postmortem brain tissue from PD patients [60]. Further mechanistic support comes from the observation that aggregation of α-Synuclein in the ER lumen induces the expression of glucose-regulated protein/immunoglobin heavy chain-binding protein (GRP78/BiP) and ATF4 in a transgenic PD mouse model that overexpress a truncated α-Synuclein (1–120) [61]. Collectively, these findings suggest that targeting the PERK/P-eIF2α pathway might yield effective therapeutics to treat PD.

A defective ubiquitin proteasome system and the accumulation of misfolded proteins have been widely linked to neuronal death in PD [62]. In cellular models of neurotoxin-induced PD, neurons derived from PERK−/− mice exhibit extensive neurite degeneration and neuronal death [63]. Several studies targeting eIF2α phosphatases also support the notion that translation repression mediated by eIF2α phosphorylation may be neuroprotective in PD models [6466]. As mutations in α-Synuclein cause autosomal dominant PD [67], the inducible expression of mutant α-Synuclein (A53T) in PC12 cells perturbs proteasomal activity and elevates ROS-mediated cytotoxicity [64]. Treating these cells with Salubrinal partially protects against α-Synuclein (A53T)-mediated cell death [64]. Salubrinal also delays disease onset and reduces motor deficits in an α-Synuclein (A53T) transgenic mouse and adenoviral-based A53T rat model [66]. The reduced ER/microsomal accumulation of toxic, oligomeric α-Synuclein is also seen following Salubrinal treatment [65,66]. However, Salubrinal treatment does not confer complete neuroprotection against α-Synuclein-induced toxicity [66]. It is unclear whether the ‘modest’ neuroprotection reflects the ability of Salubrinal to inhibit both GADD34 and CReP or its poor pharmacological properties, but the further evaluation of the GADD34-selective inhibitors, Guanabenz and Sephin [36,37], in these PD models is eagerly awaited.

Amyotrophic lateral sclerosis

ALS is an adult-onset neurodegenerative disease characterized by the loss of motor neurons in the spinal cord, brain stem and cerebral cortex, leading to progressive muscular weakness and death following respiratory failure [68]. Approximately 10% of ALS cases are familial (FALS) with mutations in the Cu/Zn superoxide dismutase (mtSOD1) accounting for 20% of FALS cases [69]. More recently, mutations in the transactive response DNA-binding protein 43 (TDP-43) and massive hexanucleotide repeat expansion in the C9ORF72 gene were shown to be causative for FALS and frontotemporal dementia (FTD) [70]. FTD is a group of disorders caused by progressive neuronal loss in both the frontal and temporal lobes of the brain [71]. Multiple studies on cellular and animal models as well as human ALS highlight that ER stress plays a key role in synaptic dysfunction and ALS pathogenesis [72,73]. Studies using transgenic mice expressing mutant human SOD1 (G37R, G85R or G93A) reveal that misfolded mtSOD1 accumulated in the ER and activated the UPR. Increased UPR is also observed in postmortem spinal cord of ALS patients [72].

The SOD1 transgenic mice (G85R/GADD34+/ΔC) carrying a loss-of-function mutation in GADD34 exhibit delayed mtSOD1 aggregation and disease onset with significantly extended lifespan compared with control G85R mice [74]. Neuroprotective effects of Salubrinal are also seen in a variety of ALS models [7478]. In these experiments, Salubrinal enhances eIF2α phosphorylation and sustains proteasome function, resulting in the reduced neurotoxicity and cell death [7577]. Saxena et al. performed in vivo longitudinal transcriptomic analyses using three different FALS mouse models following the administration of Salubrinal. Their results highlight that cell type-specific ER stress responses influences the progression of disease and Salubrinal delays disease progression at both early and late stages of disease [79]. Salubrinal also reduces TDP-43-induced neurotoxicity in Caenorhabditis elegans and zebra fish expressing ALS-associated mutant TDP-43 proteins [80].

Guanabenz reduces neuropathological outcomes, such as motor neuron loss, astrocytosis and microgliosis, in SOD1(G93A) mice at 150 days of age [81,82]. On the other hand, a recent study in SOD1(G93A) male mice points to the potential adverse effects of Guanabenz. Using two different modes of drug delivery treatment regimens (continuous infusion using subcutaneous mini-pump or intraperitoneal injections), these investigators show that Guanabenz accelerates disease onset and shortens the lifespan of the SOD1(G93A) mice. It is speculated that these unexpected untoward effects of Guanabenz result from the α2-adrenergic receptor agonist actions of the drug or its combined actions with medetomidine, a component of the anesthesia cocktail [83]. This issue was, however, addressed by the use of Sephin 1, a Guanabenz analog that lacks α2-adrenergic agonist activity [37]. Sephin 1 selectively inhibits GADD34-containing eIF2α phosphatase, similar to Guanabenz, and reduces the accumulation of mSOD1 aggregates, alleviating ER stress and motor deficits in a fast progressing ALS mouse model [37].

Huntington's disease

HD, a monogenic, autosomal dominant, progressive neurodegenerative disorder, is caused by CAG trinucleotide repeat expansion (n > 35) in the first exon of the Huntingtin (Htt) gene [84]. This genetic mutation results in the expansion of the polyglutamine tract near the amino terminus of the Htt protein, leading to protein misfolding and aggregation [85,86]. HD is characterized by the selective loss of neurons in the basal ganglia and cerebral cortex [87]. Studies in HD mice models indicate that mutant Htt protein expression affects different stages of secretory pathway, leading to protein misfolding and chronic ER stress [88,89]. Moreover, a growing body of evidence supports the activation of UPR, impairment of the ubiquitin–proteasome system and defective ERAD in HD pathogenesis [8993].

Several UPR-modulating strategies have been explored to counteract the toxic effect of chronic ER stress in HD [94,95]. For example, Salubrinal treatment of PC6.3 neuronal cells expressing Htt exon-1 with extended polyQ repeats alleviated ER stress, reduced protein aggregation and counteracts the cell death seen in these cells in the absence of the drug [96]. However, Guanabenz only partially rescues tunicamycin-induced toxicity in a stable murine striatal cell line expressing polyQ-expanded Htt (STHdhQ111/111) [97]. As failures in autophagy including cargo recognition have been reported in HD [98,99], it may be important to explore whether activation of autophagy accounts for the differences in outcome seen with the inhibition of the eIF2α phosphatases.

Prion disease

Creutzfeldt–Jakob disease (CJD) is characterized by the spongiform degeneration of the brain owing to the accumulation of misfolded and infectious prion protein (PrP) [100]. Based on the study of Tg37 mice overexpressing PrP and infected with Rocky Mountain laboratory prion at 12 weeks, UPR activation is clearly observed [101,102]. The sustained translational repression mediated by the progressive increase in eIF2α phosphorylation is associated with synaptic loss and neurodegeneration [101]. Lentiviral expression of GADD34 [101] and treatment with the PERK inhibitor GSK2606414 [103] reduce P-eIF2α levels, curtail translational repression and provide neuroprotection throughout the mouse brain. In contrast, the inhibition of eIF2α phosphatases by Salubrinal increases P-eIF2α levels and exacerbates prion disease, significantly shortening lifespan in this prion mouse model [102]. When compared with GSK2606414, which results in pancreatic toxicity in the prion-diseased mice [29], ISRIB provides effective neuroprotection in the prion mice without any hint of pancreatic damage [28]. However, these studies also highlight some limitations of this compound, namely its poor solubility and unexplained weight loss in animals administered with ISRIB. It is anticipated that ongoing medicinal chemistry, aimed at improving the pharmacological properties of ISRIB [104], may overcome some of these concerns.

Concluding remarks

The focus of this review is on the potential impact of pharmacological modulation of P-eIF2α levels in the brain, specifically the relative merits of inhibiting PERK or the GADD34-containing eIF2α phosphatase, on major neurodegenerative diseases. In this context, one remains concerned about the reliable modeling of human aging-related diseases in mice, whose shorter lifespan suggests that many models may represent accelerated or aggressive forms of disease, raising the bar for evaluating potential therapeutics. Regardless, both classes of P-eIF2α modifiers show some capacity to ameliorate disease, possibly resetting the balance in this critical homeostatic pathway. Our discussion highlights the liability of current PERK inhibitors when used alone as, by targeting the pancreas, these compounds elevate blood sugar levels and may, with long-term use, precipitate diabetes. By comparison, the GADD34 inhibitors appear relatively benign. However, with the new appreciation for GADD34's function in regulating mRNA translation in healthy or unstressed cells as well as stressed or diseased cells, a careful evaluation of the potential side effects is required, particularly with the chronic use of these compounds as likely necessary to manage human neurodegenerative disease. Finally, there comes the question of how or why might the inhibition of an eIF2α kinase or an eIF2α phosphatase elicits beneficial effects in some models of a neurodegenerative disease but not in others. Here, one can only speculate as we currently lack the molecular fingerprints for disease onset or progression. With the recognition that ER stress elicits an extensive remodeling of the cellular translatome and that deregulation of mRNA translation may be a critical contributor to pathogenesis of diseases, such as PD [105], the current focus is on the genome-wide analysis of mRNA translation in the deceased brain regions [106,107]. These studies may not only provide crucial biomarkers defining the stage of disease but also be useful in guiding therapies with UPR-modifying drugs to achieve the desired outcome.

Abbreviations

     
  • AD

    Alzheimer's disease

  •  
  • ALS

    amyotrophic lateral sclerosis

  •  
  • APP

    amyloid precursor protein

  •  
  • CReP

    constitutive repressor of eIF2α phosphorylation

  •  
  • ER

    endoplasmic reticulum

  •  
  • FALS

    familial ALS

  •  
  • FTD

    frontotemporal dementia

  •  
  • GADD34

    growth arrest and DNA damage-inducible transcript 34

  •  
  • HD

    Huntington's disease

  •  
  • Htt

    Huntingtin

  •  
  • IFNAR1

    type 1 interferon receptor

  •  
  • mGluRs

    metabotropic glutamate receptor

  •  
  • mtSOD1

    mutations in the Cu/Zn superoxide dismutase

  •  
  • PD

    Parkinson's disease

  •  
  • PP1

    protein phosphatase-1

  •  
  • PrP

    prion protein

  •  
  • TDP-43

    transactive response DNA-binding protein 43

  •  
  • UPR

    unfolded protein response.

Funding

The work in this laboratory is supported by the NMRC Translational Clinical Research Flagship Award [NMRC/TCR/013-NNI/2014], ‘National Parkinson's Disease Translational Clinical Research Programme’, GlaxoSmithKline Academic Center of Excellence Award and A*STAR Translational and Clinical Research Partnership [grant ACP0113683].

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

References

References
1
Soto
,
C.
and
Estrada
,
L.D.
(
2008
)
Protein misfolding and neurodegeneration
.
Arch. Neurol.
65
,
184
189
doi:
2
Hetz
,
C.
and
Mollereau
,
B.
(
2014
)
Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases
.
Nat. Rev. Neurosci.
15
,
233
249
doi:
3
Placido
,
A.I.
,
Pereira
,
C.M.F.
,
Duarte
,
A.I.
,
Candeias
,
E.
,
Correia
,
S.C.
,
Carvalho
,
C.
et al. 
(
2015
)
Modulation of endoplasmic reticulum stress: an opportunity to prevent neurodegeneration?
CNS Neurol. Disord. Drug Targets
14
,
518
533
doi:
4
Scheper
,
W.
and
Hoozemans
,
J.J.M.
(
2015
)
The unfolded protein response in neurodegenerative diseases: a neuropathological perspective
.
Acta Neuropathol.
130
,
315
331
doi:
5
Ron
,
D.
and
Walter
,
P.
(
2007
)
Signal integration in the endoplasmic reticulum unfolded protein response
.
Nat. Rev. Mol. Cell Biol.
8
,
519
529
doi:
6
Kaushik
,
S.
and
Cuervo
,
A.M.
(
2015
)
Proteostasis and aging
.
Nat. Med.
21
,
1406
1415
doi:
7
Yun
,
C.
,
Stanhill
,
A.
,
Yang
,
Y.
,
Zhang
,
Y.
,
Haynes
,
C.M.
,
Xu
,
C.-F.
et al. 
(
2008
)
Proteasomal adaptation to environmental stress links resistance to proteotoxicity with longevity in Caenorhabditis elegans
.
Proc. Natl Acad. Sci. U.S.A.
105
,
7094
7099
doi:
8
De Strooper
,
B.
and
Karran
,
E.
(
2016
)
The cellular phase of Alzheimer's disease
.
Cell
164
,
603
615
doi:
9
Mercado
,
G.
,
Castillo
,
V.
,
Vidal
,
R.
and
Hetz
,
C.
(
2015
)
ER proteostasis disturbances in Parkinson's disease: novel insights
.
Front. Aging Neurosci.
7
,
39
doi:
10
Kaus
,
A.
and
Sareen
,
D.
(
2015
)
ALS patient stem cells for unveiling disease signatures of motoneuron susceptibility: perspectives on the deadly mitochondria, ER stress and calcium triad
.
Front. Cell Neurosci.
9
,
448
doi:
11
Ling
,
S.-C.
,
Polymenidou
,
M.
and
Cleveland
,
D.W.
(
2013
)
Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis
.
Neuron
79
,
416
438
doi:
12
Saudou
,
F.
and
Humbert
,
S.
(
2016
)
The biology of Huntingtin
.
Neuron
89
,
910
926
doi:
13
Wolff
,
S.
,
Weissman
,
J.S.
and
Dillin
,
A.
(
2014
)
Differential scales of protein quality control
.
Cell
157
,
52
64
doi:
14
Lim
,
J.H.
,
Lee
,
H.J.
and
Jung
,
M.H.
(
2009
)
Coupling mitochondrial dysfunction to endoplasmic reticulum stress response: a molecular mechanisms leading to hepatic insulin resistance
.
Cell Signal.
21
,
169
177
doi:
15
Roy
,
S.
,
Trudeau
,
K.
,
Roy
,
S.
,
Tien
,
T.
and
Barrette
,
K.F.
(
2013
)
Mitochondrial dysfunction and endoplasmic reticulum stress in diabetic retinopathy: mechanistic insights into high glucose-induced retinal cell death
.
Curr. Clin. Pharmacol.
8
,
278
284
doi:
16
Suliman
,
H.B.
and
Piantadosi
,
C.A.
(
2016
)
Mitochondrial quality control as a therapeutic target
.
Pharmacol. Rev.
68
,
20
48
doi:
17
Perez-Pinzon
,
M.A.
,
Stetler
,
R.A.
and
Fiskum
,
G.
(
2012
)
Novel mitochondrial targets for neuroprotection
.
J. Cereb. Blood Flow Metab.
32
,
1362
1376
doi:
18
Fullwood
,
M.J.
,
Zhou
,
W.
and
Shenolikar
,
S.
(
2012
)
Targeting phosphorylation of eukaryotic initiation factor-2α to treat human disease
.
Prog. Mol. Biol. Transl. Sci.
106
,
75
106
doi:
19
Hetz
,
C.
,
Chevet
,
E.
and
Harding
,
H.P.
(
2013
)
Targeting the unfolded protein response in disease
.
Nat. Rev. Drug Discov.
12
,
703
719
doi:
20
Plate
,
L.
,
Paxman
,
R.J.
,
Wiseman
,
R.L.
and
Kelly
,
J.W.
(
2016
)
Modulating protein quality control
.
eLife
5
,
e18431
doi:
21
Smith
,
H.L.
and
Mallucci
,
G.R.
(
2016
)
The unfolded protein response: mechanisms and therapy of neurodegeneration
.
Brain
139
,
2113
2121
doi:
22
Costa-Mattioli
,
M.
,
Sossin
,
W.S.
,
Klann
,
E.
and
Sonenberg
,
N.
(
2009
)
Translational control of long-lasting synaptic plasticity and memory
.
Neuron
61
,
10
26
doi:
23
Delépine
,
M.
,
Nicolino
,
M.
,
Barrett
,
T.
,
Golamaully
,
M.
,
Lathrop
,
G.M.
and
Julier
,
C.
(
2000
)
EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott–Rallison syndrome
.
Nat. Genet.
25
,
406
409
doi:
24
Zhang
,
P.
,
McGrath
,
B.
,
Li
,
S.
,
Frank
,
A.
,
Zambito
,
F.
,
Reinert
,
J.
et al. 
(
2002
)
The PERK eukaryotic initiation factor 2α kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas
.
Mol. Cell Biol.
22
,
3864
3874
doi:
25
Scheper
,
W.
and
Hoozemans
,
J.J.M.
(
2013
)
A new PERKspective on neurodegeneration
.
Sci. Transl. Med.
5
,
206fs37
doi:
26
Scheuner
,
D.
,
Song
,
B.
,
McEwen
,
E.
,
Liu
,
C.
,
Laybutt
,
R.
,
Gillespie
,
P.
et al. 
(
2001
)
Translational control is required for the unfolded protein response and in vivo glucose homeostasis
.
Mol. Cell
7
,
1165
1176
doi:
27
Yu
,
Q.
,
Zhao
,
B.
,
Gui
,
J.
,
Katlinski
,
K.V.
,
Brice
,
A.
,
Gao
,
Y.
et al. 
(
2015
)
Type I interferons mediate pancreatic toxicities of PERK inhibition
.
Proc. Natl Acad. Sci. U.S.A.
112
,
15420
15425
doi:
28
Sidrauski
,
C.
,
McGeachy
,
A.M.
,
Ingolia
,
N.T.
and
Walter
,
P.
(
2015
)
The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly
.
eLife
4
,
e05033
doi:
29
Halliday
,
M.
,
Radford
,
H.
,
Sekine
,
Y.
,
Moreno
,
J.
,
Verity
,
N.
,
le Quesne
,
J.
et al. 
(
2015
)
Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity
.
Cell Death Dis.
6
,
e1672
doi:
30
Wiseman
,
R.L.
and
Balch
,
W.E.
(
2005
)
A new pharmacology: drugging stressed folding pathways
.
Trends Mol. Med.
11
,
347
350
doi:
31
Harding
,
H.P.
,
Zhang
,
Y.
,
Scheuner
,
D.
,
Chen
,
J.-J.
,
Kaufman
,
R.J.
and
Ron
,
D.
(
2009
)
Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2α (eIF2α) dephosphorylation in mammalian development
.
Proc. Natl Acad. Sci. U.S.A.
106
,
1832
1837
doi:
32
Abdulkarim
,
B.
,
Nicolino
,
M.
,
Igoillo-Esteve
,
M.
,
Daures
,
M.
,
Romero
,
S.
,
Philippi
,
A.
et al. 
(
2015
)
A missense mutation in PPP1R15B causes a syndrome including diabetes, short stature, and microcephaly
.
Diabetes
64
,
3951
3962
doi:
33
Kernohan
,
K.D.
,
Tétreault
,
M.
,
Liwak-Muir
,
U.
,
Geraghty
,
M.T.
,
Qin
,
W.
,
Venkateswaran
,
S.
et al. 
(
2015
)
Homozygous mutation in the eukaryotic translation initiation factor 2α phosphatase gene, PPP1R15B, is associated with severe microcephaly, short stature and intellectual disability
.
Hum. Mol. Genet.
24
,
6293
6300
doi:
34
Choy
,
M.S.
,
Yusoff
,
P.
,
Lee
,
I.C.
,
Newton
,
J.C.
,
Goh
,
C.W.
,
Page
,
R.
et al. 
(
2015
)
Structural and functional analysis of the GADD34:PP1 eIF2α phosphatase
.
Cell Rep.
11
,
1885
1891
doi:
35
Boyce
,
M.
,
Bryant
,
K.F.
,
Jousse
,
C.
,
Long
,
K.
,
Harding
,
H.P.
,
Scheuner
,
D.
et al. 
(
2005
)
A selective inhibitor of eIF2α dephosphorylation protects cells from ER stress
.
Science
307
,
935
939
doi:
36
Tsaytler
,
P.
,
Harding
,
H.P.
,
Ron
,
D.
and
Bertolotti
,
A.
(
2011
)
Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis
.
Science
332
,
91
94
doi:
37
Das
,
I.
,
Krzyzosiak
,
A.
,
Schneider
,
K.
,
Wrabetz
,
L.
,
D'Antonio
,
M.
,
Barry
,
N.
et al. 
(
2015
)
Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit
.
Science
348
,
239
242
doi:
38
Reid
,
D.W.
,
Tay
,
A.S.L.
,
Sundaram
,
J.R.
,
Lee
,
I.C.J.
,
Chen
,
Q.
,
George
,
S.E.
et al. 
(
2016
)
Complementary roles of GADD34- and CReP-containing eukaryotic initiation factor 2α phosphatases during the unfolded protein response
.
Mol. Cell Biol.
36
,
1868
1880
doi:
39
Reid
,
D.W.
,
Chen
,
Q.
,
Tay
,
A.S.L.
,
Shenolikar
,
S.
and
Nicchitta
,
C.V.
(
2014
)
The unfolded protein response triggers selective mRNA release from the endoplasmic reticulum
.
Cell
158
,
1362
1374
doi:
40
Brush
,
M.H.
and
Shenolikar
,
S.
(
2008
)
Control of cellular GADD34 levels by the 26S proteasome
.
Mol. Cell Biol.
28
,
6989
7000
doi:
41
Selkoe
,
D.J.
and
Hardy
,
J.
(
2016
)
The amyloid hypothesis of Alzheimer's disease at 25 years
.
EMBO Mol. Med.
8
,
595
608
doi:
42
Chang
,
R.C.C.
,
Wong
,
A.K.Y.
,
Ng
,
H.-K.
and
Hugon
,
J.
(
2002
)
Phosphorylation of eukaryotic initiation factor-2α (eIF2α) is associated with neuronal degeneration in Alzheimer's disease
.
Neuroreport
13
,
2429
2432
doi:
43
Devi
,
L.
and
Ohno
,
M.
(
2010
)
Phospho-eIF2α level is important for determining abilities of BACE1 reduction to rescue cholinergic neurodegeneration and memory defects in 5XFAD mice
.
PLoS ONE
5
,
e12974
doi:
44
Kim
,
H.-S.
,
Choi
,
Y.
,
Shin
,
K.-Y.
,
Joo
,
Y.
,
Lee
,
Y.-K.
,
Jung
,
S.Y.
et al. 
(
2007
)
Swedish amyloid precursor protein mutation increases phosphorylation of eIF2α in vitro and in vivo
.
J. Neurosci. Res.
85
,
1528
1537
doi:
45
Page
,
G.
,
Rioux Bilan
,
A.
,
Ingrand
,
S.
,
Lafay-Chebassier
,
C.
,
Pain
,
S.
,
Perault Pochat
,
M.C.
et al. 
(
2006
)
Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer's disease
.
Neuroscience
139
,
1343
1354
doi:
46
O'Connor
,
T.
,
Sadleir
,
K.R.
,
Maus
,
E.
,
Velliquette
,
R.A.
,
Zhao
,
J.
,
Cole
,
S.L.
et al. 
(
2008
)
Phosphorylation of the translation initiation factor eIF2α increases BACE1 levels and promotes amyloidogenesis
.
Neuron
60
,
988
1009
doi:
47
Ma
,
T.
,
Trinh
,
M.A.
,
Wexler
,
A.J.
,
Bourbon
,
C.
,
Gatti
,
E.
,
Pierre
,
P.
et al. 
(
2013
)
Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits
.
Nat. Neurosci.
16
,
1299
1305
doi:
48
Devi
,
L.
and
Ohno
,
M.
(
2014
)
PERK mediates eIF2α phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer's disease
.
Neurobiol. Aging
35
,
2272
2281
doi:
49
Baleriola
,
J.
,
Walker
,
C.A.
,
Jean
,
Y.Y.
,
Crary
,
J.F.
,
Troy
,
C.M.
,
Nagy
,
P.L.
et al. 
(
2014
)
Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions
.
Cell
158
,
1159
1172
doi:
50
Honjo
,
Y.
,
Ayaki
,
T.
,
Tomiyama
,
T.
,
Horibe
,
T.
,
Ito
,
H.
,
Mori
,
H.
et al. 
(
2015
)
Increased GADD34 in oligodendrocytes in Alzheimer's disease
.
Neurosci. Lett.
602
,
50
55
doi:
51
Lee
,
D.Y.
,
Lee
,
K.-S.
,
Lee
,
H.J.
,
Kim
,
D.H.
,
Noh
,
Y.H.
,
Yu
,
K.
et al. 
(
2010
)
Activation of PERK signaling attenuates aβ-mediated ER stress
.
PLoS ONE
5
,
e10489
doi:
52
Huang
,
X.
,
Chen
,
Y.
,
Zhang
,
H.
,
Ma
,
Q.
,
Zhang
,
Y.W.
and
Xu
,
H.
(
2012
)
Salubrinal attenuates β-amyloid-induced neuronal death and microglial activation by inhibition of the NF-κB pathway
.
Neurobiol. Aging
33
,
1007.e9
e17
 doi:
53
Casal
,
C.
,
Serratosa
,
J.
and
Tusell
,
J.M.
(
2004
)
Effects of β-AP peptides on activation of the transcription factor NF-κB and in cell proliferation in glial cell cultures
.
Neurosci. Res.
48
,
315
323
doi:
54
Di Prisco
,
G.V.
,
Huang
,
W.
,
Buffington
,
S.A.
,
Hsu
,
C.-C.
,
Bonnen
,
P.E.
,
Placzek
,
A.N.
et al. 
(
2014
)
Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α
.
Nat. Neurosci.
17
,
1073
1082
doi:
55
Lüscher
,
C.
and
Huber
,
K.M.
(
2010
)
Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease
.
Neuron
65
,
445
459
doi:
56
Lesage
,
S.
and
Brice
,
A.
(
2009
)
Parkinson's disease: from monogenic forms to genetic susceptibility factors
.
Hum. Mol. Genet.
18
,
R48
R59
doi:
57
Spillantini
,
M.G.
,
Schmidt
,
M.L.
,
Lee
,
V.M.-Y.
,
Trojanowski
,
J.Q.
,
Jakes
,
R.
and
Goedert
,
M.
(
1997
)
α-Synuclein in Lewy bodies
.
Nature
388
,
839
840
doi:
58
Athauda
,
D.
and
Foltynie
,
T.
(
2015
)
The ongoing pursuit of neuroprotective therapies in Parkinson disease
.
Nat. Rev. Neurol.
11
,
25
40
doi:
59
Chung
,
C.Y.
,
Khurana
,
V.
,
Auluck
,
P.K.
,
Tardiff
,
D.F.
,
Mazzulli
,
J.R.
,
Soldner
,
F.
et al. 
(
2013
)
Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons
.
Science
342
,
983
987
doi:
60
Hoozemans
,
J.J.
,
van Haastert
,
E.S.
,
Eikelenboom
,
P.
,
de Vos
,
R.A.I.
,
Rozemuller
,
J.M.
and
Scheper
,
W.
(
2007
)
Activation of the unfolded protein response in Parkinson's disease
.
Biochem. Biophys. Res. Commun.
354
,
707
711
doi:
61
Bellucci
,
A.
,
Navarria
,
L.
,
Zaltieri
,
M.
,
Falarti
,
E.
,
Bodei
,
S.
,
Sigala
,
S.
et al. 
(
2011
)
Induction of the unfolded protein response by α-synuclein in experimental models of Parkinson's disease
.
J. Neurochem.
116
,
588
605
doi:
62
Lim
,
K.-L.
(
2007
)
Ubiquitin-proteasome system dysfunction in Parkinson's disease: current evidence and controversies
.
Expert Rev. Proteomics
4
,
769
781
doi:
63
Ryu
,
E.J.
,
Harding
,
H.P.
,
Angelastro
,
J.M.
,
Vitolo
,
O.V.
,
Ron
,
D.
and
Greene
,
L.A.
(
2002
)
Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson's disease
.
J. Neurosci.
22
,
10690
10698
PMID:
[PubMed]
64
Smith
,
W.W.
,
Jiang
,
H.
,
Pei
,
Z.
,
Tanaka
,
Y.
,
Morita
,
H.
,
Sawa
,
A.
et al. 
(
2005
)
Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant α-synuclein-induced toxicity
.
Hum. Mol. Genet.
14
,
3801
3811
doi:
65
Colla
,
E.
,
Jensen
,
P.H.
,
Pletnikova
,
O.
,
Troncoso
,
J.C.
,
Glabe
,
C.
and
Lee
,
M.K.
(
2012
)
Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo
.
J. Neurosci.
32
,
3301
3305
doi:
66
Colla
,
E.
,
Coune
,
P.
,
Liu
,
Y.
,
Pletnikova
,
O.
,
Troncoso
,
J.C.
,
Iwatsubo
,
T.
et al. 
(
2012
)
Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo
.
J. Neurosci.
32
,
3306
3320
doi:
67
Polymeropoulos
,
M.H.
,
Lavedan
,
C.
,
Leroy
,
E.
,
Ide
,
S.E.
,
Dehejia
,
A.
,
Dutra
,
A.
et al. 
(
1997
)
Mutation in the α-synuclein gene identified in families with Parkinson's disease
.
Science
276
,
2045
2047
doi:
68
Kiernan
,
M.C.
,
Vucic
,
S.
,
Cheah
,
B.C.
,
Turner
,
M.R.
,
Eisen
,
A.
,
Hardiman
,
O.
et al. 
(
2011
)
Amyotrophic lateral sclerosis
.
Lancet
377
,
942
955
doi:
69
Rosen
,
D.R.
,
Siddique
,
T.
,
Patterson
,
D.
,
Figlewicz
,
D.A.
,
Sapp
,
P.
,
Hentati
,
A.
et al. 
(
1993
)
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis
.
Nature
362
,
59
62
doi:
70
Renton
,
A.E.
,
Chiò
,
A.
and
Traynor
,
B.J.
(
2014
)
State of play in amyotrophic lateral sclerosis genetics
.
Nat. Neurosci.
17
,
17
23
doi:
71
Bak
,
T.H.
(
2010
)
Motor neuron disease and frontotemporal dementia: one, two, or three diseases?
Ann. Indian Acad. Neurol.
13
,
S81
S88
doi:
72
Walker
,
A.K.
and
Atkin
,
J.D.
(
2011
)
Stress signaling from the endoplasmic reticulum: a central player in the pathogenesis of amyotrophic lateral sclerosis
.
IUBMB Life
63
,
754
763
doi:
73
Matus
,
S.
,
Valenzuela
,
V.
,
Medinas
,
D.B.
and
Hetz
,
C.
(
2013
)
ER dysfunction and protein folding stress in ALS
.
Int. J. Cell Biol.
2013
,
Article ID 674751
doi:
74
Wang
,
L.
,
Popko
,
B.
and
Roos
,
R.P.
(
2014
)
An enhanced integrated stress response ameliorates mutant SOD1-induced ALS
.
Hum. Mol. Genet.
23
,
2629
2638
doi:
75
Moumen
,
A.
,
Virard
,
I.
and
Raoul
,
C.
(
2011
)
Accumulation of wildtype and ALS-linked mutated VAPB impairs activity of the proteasome
.
PLoS ONE
6
,
e26066
doi:
76
Zhang
,
Y.-J.
,
Jansen-West
,
K.
,
Xu
,
Y.-F.
,
Gendron
,
T.F.
,
Bieniek
,
K.F.
,
Lin
,
W.-L.
et al. 
(
2014
)
Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress
.
Acta Neuropathol.
128
,
505
524
doi:
77
Oh
,
Y.K.
,
Shin
,
K.S.
,
Yuan
,
J.
and
Kang
,
S.J.
(
2008
)
Superoxide dismutase 1 mutants related to amyotrophic lateral sclerosis induce endoplasmic stress in neuro2a cells
.
J. Neurochem.
104
,
993
1005
doi:
78
Walker
,
A.K.
,
Soo
,
K.Y.
,
Sundaramoorthy
,
V.
,
Parakh
,
S.
,
Ma
,
Y.
,
Farg
,
M.A.
et al. 
(
2013
)
ALS-associated TDP-43 induces endoplasmic reticulum stress, which drives cytoplasmic TDP-43 accumulation and stress granule formation
.
PLoS ONE
8
,
e81170
doi:
79
Saxena
,
S.
,
Cabuy
,
E.
and
Caroni
,
P.
(
2009
)
A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice
.
Nat. Neurosci.
12
,
627
636
doi:
80
Vaccaro
,
A.
,
Patten
,
S.A.
,
Aggad
,
D.
,
Julien
,
C.
,
Maios
,
C.
,
Kabashi
,
E.
et al. 
(
2013
)
Pharmacological reduction of ER stress protects against TDP-43 neuronal toxicity in vivo
.
Neurobiol. Dis.
55
,
64
75
doi:
81
Wang
,
L.
,
Popko
,
B.
,
Tixier
,
E.
and
Roos
,
R.P.
(
2014
)
Guanabenz, which enhances the unfolded protein response, ameliorates mutant SOD1-induced amyotrophic lateral sclerosis
.
Neurobiol. Dis.
71
,
317
324
doi:
82
Jiang
,
H.-Q.
,
Ren
,
M.
,
Jiang
,
H.-Z.
,
Wang
,
J.
,
Zhang
,
J.
,
Yin
,
X.
et al. 
(
2014
)
Guanabenz delays the onset of disease symptoms, extends lifespan, improves motor performance and attenuates motor neuron loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis
.
Neuroscience
277
,
132
138
doi:
83
Vieira
,
F.G.
,
Ping
,
Q.
,
Moreno
,
A.J.
,
Kidd
,
J.D.
,
Thompson
,
K.
,
Jiang
,
B.
et al. 
(
2015
)
Guanabenz treatment accelerates disease in a mutant SOD1 mouse model of ALS
.
PLoS ONE
10
,
e0135570
doi:
84
Scherzinger
,
E.
,
Sittler
,
A.
,
Schweiger
,
K.
,
Heiser
,
V.
,
Lurz
,
R.
,
Hasenbank
,
R.
et al. 
(
1999
)
Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology
.
Proc. Natl Acad. Sci. U.S.A.
96
,
4604
4609
doi:
85
DiFiglia
,
M.
,
Sapp
,
E.
,
Chase
,
K.O.
,
Davies
,
S.W.
,
Bates
,
G.P.
,
Vonsattel
,
J.P.
et al. 
(
1997
)
Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain
.
Science
277
,
1990
1993
doi:
86
Davies
,
S.W.
,
Turmaine
,
M.
,
Cozens
,
B.A.
,
DiFiglia
,
M.
,
Sharp
,
A.H.
,
Ross
,
C.A.
et al. 
(
1997
)
Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation
.
Cell
90
,
537
548
doi:
87
Han
,
I.
,
You
,
Y.
,
Kordower
,
J.H.
,
Brady
,
S.T.
and
Morfini
,
G.A.
(
2010
)
Differential vulnerability of neurons in Huntington's disease: the role of cell type-specific features
.
J. Neurochem.
113
,
1073
1091
doi:
88
Noh
,
J.-Y.
,
Lee
,
H.
,
Song
,
S.
,
Kim
,
N.S.
,
Im
,
W.
,
Kim
,
M.
et al. 
(
2009
)
SCAMP5 links endoplasmic reticulum stress to the accumulation of expanded polyglutamine protein aggregates via endocytosis inhibition
.
J. Biol. Chem.
284
,
11318
11325
doi:
89
Carnemolla
,
A.
,
Fossale
,
E.
,
Agostoni
,
E.
,
Michelazzi
,
S.
,
Calligaris
,
R.
,
De Maso
,
L.
et al. 
(
2009
)
Rrs1 is involved in endoplasmic reticulum stress response in Huntington disease
.
J. Biol. Chem.
284
,
18167
18173
doi:
90
Duennwald
,
M.L.
and
Lindquist
,
S.
(
2008
)
Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity
.
Genes Dev.
22
,
3308
3319
doi:
91
Leitman
,
J.
,
Ulrich Hartl
,
F.
and
Lederkremer
,
G.Z.
(
2013
)
Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress
.
Nat. Commun.
4
,
2753
doi:
92
Bennett
,
E.J.
,
Shaler
,
T.A.
,
Woodman
,
B.
,
Ryu
,
K.-Y.
,
Zaitseva
,
T.S.
,
Becker
,
C.H.
et al. 
(
2007
)
Global changes to the ubiquitin system in Huntington's disease
.
Nature
448
,
704
708
doi:
93
Vidal
,
R.
,
Caballero
,
B.
,
Couve
,
A.
and
Hetz
,
C.
(
2011
)
Converging pathways in the occurrence of endoplasmic reticulum (ER) stress in Huntington's disease
.
Curr. Mol. Med.
11
,
1
12
doi:
94
Ferrante
,
R.J.
,
Kubilus
,
J.K.
,
Lee
,
J.
,
Ryu
,
H.
,
Beesen
,
A.
,
Zucker
,
B.
et al. 
(
2003
)
Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice
.
J. Neurosci.
23
,
9418
9427
PMID:
[PubMed]
95
Cho
,
K.J.
,
Cheon
,
S.Y.
and
Kim
,
G.W.
(
2016
)
Apoptosis signal-regulating kinase 1 mediates striatal degeneration via the regulation of C1q
.
Sci. Rep.
6
,
18840
doi:
96
Reijonen
,
S.
,
Putkonen
,
N.
,
Nørremolle
,
A.
,
Lindholm
,
D.
and
Korhonen
,
L.
(
2008
)
Inhibition of endoplasmic reticulum stress counteracts neuronal cell death and protein aggregation caused by N-terminal mutant huntingtin proteins
.
Exp. Cell Res.
314
,
950
960
doi:
97
Leitman
,
J.
,
Barak
,
B.
,
Benyair
,
R.
,
Shenkman
,
M.
,
Ashery
,
U.
,
Hartl
,
F.U.
et al. 
(
2014
)
ER stress-induced eIF2-α phosphorylation underlies sensitivity of striatal neurons to pathogenic huntingtin
.
PLoS ONE
9
,
e90803
doi:
98
Martin
,
D.D.O.
,
Ladha
,
S.
,
Ehrnhoefer
,
D.E.
and
Hayden
,
M.R.
(
2015
)
Autophagy in Huntington disease and huntingtin in autophagy
.
Trends Neurosci.
38
,
26
35
doi:
99
Martinez-Vicente
,
M.
,
Talloczy
,
Z.
,
Wong
,
E.
,
Tang
,
G.
,
Koga
,
H.
,
Kaushik
,
S.
et al. 
(
2010
)
Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease
.
Nat. Neurosci.
13
,
567
576
doi:
100
Prusiner
,
S.B.
(
1998
)
The prion diseases
.
Brain Pathol.
8
,
499
513
doi:
101
Moreno
,
J.A.
,
Radford
,
H.
,
Peretti
,
D.
,
Steinert
,
J.R.
,
Verity
,
N.
,
Martin
,
M.G.
et al. 
(
2012
)
Sustained translational repression by eIF2α-P mediates prion neurodegeneration
.
Nature
485
,
507
511
doi:
102
Moreno
,
J.A.
,
Halliday
,
M.
,
Molloy
,
C.
,
Radford
,
H.
,
Verity
,
N.
,
Axten
,
J.M.
et al. 
(
2013
)
Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice
.
Sci. Transl. Med.
5
,
206ra138
doi:
103
Axten
,
J.M.
,
Medina
,
J.R.
,
Feng
,
Y.
,
Shu
,
A.
,
Romeril
,
S.P.
,
Grant
,
S.W.
et al. 
(
2012
)
Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)
.
J. Med. Chem.
55
,
7193
7207
doi:
104
Hearn
,
B.R.
,
Jaishankar
,
P.
,
Sidrauski
,
C.
,
Tsai
,
J.C.
,
Vedantham
,
P.
,
Fontaine
,
S.D.
et al. 
(
2016
)
Structure-activity studies of bis-O-arylglycolamides: inhibitors of the integrated stress response
.
Chem. Med. Chem.
11
,
870
880
doi:
105
Taymans
,
J.-M.
,
Nkiliza
,
A.
and
Chartier-Harlin
,
M.-C.
(
2015
)
Deregulation of protein translation control, a potential game-changing hypothesis for Parkinson's disease pathogenesis
.
Trends Mol. Med.
21
,
466
472
doi:
106
Rooijers
,
K.
,
Loayza-Puch
,
F.
,
Nijtmans
,
L.G.
and
Agami
,
R.
(
2013
)
Ribosome profiling reveals features of normal and disease-associated mitochondrial translation
.
Nat. Commun.
4
,
2886
doi:
107
Brichta
,
L.
,
Shin
,
W.
,
Jackson-Lewis
,
V.
,
Blesa
,
J.
,
Yap
,
E.-L.
,
Walker
,
Z.
et al. 
(
2015
)
Identification of neurodegenerative factors using translatome-regulatory network analysis
.
Nat. Neurosci.
18
,
1325
1333
doi: