TDP-43 (TAR DNA-binding protein 43) is an hnRNP (heterogeneous nuclear ribonucleoprotein) protein whose role in cellular processes has come to the forefront of neurodegeneration research after the observation that it is the main component of brain inclusions in ALS (amyotrophic lateral sclerosis) and FTLD (frontotemporal lobar degeneration) patients. Functionally, this aberrant aggregation and mislocalization implies that, in the affected neurons, transcripts regulated by TDP-43 may be altered. Since then, a considerable amount of data has been gathered on TDP-43 interactions and on the genes that are influenced by its absence or overexpression. At present, however, most of these data come from high-throughput searches, making it problematic to separate the direct effects of TDP-43 from secondary misregulations occurring at different levels of the gene expression process. Furthermore, our knowledge of the biochemistry of TDP-43, its RNA-binding characteristics, its nuclear and cytoplasmic targets, and the details of its interactions with other proteins is still incomplete. The understanding of these features could hold the key for uncovering TDP-43′s role in ALS and FTLD pathogenesis. We describe in the present paper our work on TDP-43 RNA binding, self-regulation and aggregation processes, and attempt to relate them to the neurodegenerative pathologies.

Introduction

TDP-43 (TAR DNA-binding protein 43) belongs to the hnRNP (heterogeneous nuclear ribonucleoprotein) family of proteins [1]. As such, the critical characteristic for its function is the RNA-binding ability that in hnRNPs can range from quite aspecific to a very well defined ribonucleotide target sequence. In addition, functional specificity is also provided in many hnRNPs by glycine-rich regions present in their sequence that mediate interaction with other protein factors. Broadly it can be said that the hnRNPs are some of the most important negative regulators of alternative splicing and their function can be generally defined as antagonistic to another class of positive splicing factors, the SR (serine/arginine)-rich proteins. However, their purpose is certainly not restricted only to splicing regulation, and members of this family can play a role in all aspects of RNA metabolism, from transcription and splicing to miRNA maturation, mRNA transport, degradation and translation.

TDP-43 has obscure beginnings; in fact, it was described in 1995 as a protein associated with HIV transcription [2] and it was only in 2001 that it was rediscovered as an hnRNP with a role in peculiar splicing systems [3]. In the successive years it was shown to be involved in functions such as mRNA stability (including its own) [46], miRNA processing [7,8], and mRNA transport and translation [911] (Figure 1A).

Schematic diagram of TDP-43 functional regions, its principal functional properties and gene expression

Figure 1
Schematic diagram of TDP-43 functional regions, its principal functional properties and gene expression

(A) Functions of TDP-43. The top panel shows a schematic representation of the TDP-43 protein structure highlighting the major domain sequences determining nuclear/cytoplasmic localization (NLS and NES) or RNA binding (RRM1 and RMM2). Q/N indicates the glycine/asparagine-rich region. (B) Schematic diagram of TDP-43 gene illustrating locations of the stop codon (tag), polyadenlation sites (pA1–pA4), TDPBR and splicing events (represented by diagonal lines that connect the coding regions) that result in mRNA species that use pA1 and pA4. Dotted vertical lines in the 3′-UTR region represent exon borders within this region introns are embodied by black horizontal lines. The resulting protein symbolized by a circle is derived principally from the mRNA species that uses pA2 as that using pA4 is largely retained in the nucleus. (C) TDP-43 autoregulation results from binding of TDP-43 protein to the TDPBR. This results in splicing of intron 7 (eliminating the possibility of using pA1) leading to an mRNA species that uses pA2 which does not translate to protein.

Figure 1
Schematic diagram of TDP-43 functional regions, its principal functional properties and gene expression

(A) Functions of TDP-43. The top panel shows a schematic representation of the TDP-43 protein structure highlighting the major domain sequences determining nuclear/cytoplasmic localization (NLS and NES) or RNA binding (RRM1 and RMM2). Q/N indicates the glycine/asparagine-rich region. (B) Schematic diagram of TDP-43 gene illustrating locations of the stop codon (tag), polyadenlation sites (pA1–pA4), TDPBR and splicing events (represented by diagonal lines that connect the coding regions) that result in mRNA species that use pA1 and pA4. Dotted vertical lines in the 3′-UTR region represent exon borders within this region introns are embodied by black horizontal lines. The resulting protein symbolized by a circle is derived principally from the mRNA species that uses pA2 as that using pA4 is largely retained in the nucleus. (C) TDP-43 autoregulation results from binding of TDP-43 protein to the TDPBR. This results in splicing of intron 7 (eliminating the possibility of using pA1) leading to an mRNA species that uses pA2 which does not translate to protein.

TDP-43 became a central player in neurochemical research when it was identified in 2006 [12] as the main component of brain inclusions in patients suffering from ALS (amyotrophic lateral sclerosis) and FTLD (frontotemporal lobar degeneration).

TDP-43 has not remained an isolated player in neurodegeneration. In fact, since its involvement in ALS and FTLD was initially described, many other RNA-binding proteins, such as FUS/TLS (fused in sarcoma/translocated in liposarcoma), hnRNPA1/A2 and other hnRNPs were found to be mutated and/or aggregated in diseased brains or muscle [13]. Similarly to TDP-43, all of them are involved in mRNA-processing steps. Even the newly discovered locus C9orf72 linked to ALS displays a G4C2 expansion that may provoke the disease by sequestering RNA-binding factor(s) [14] as described for myotonic dystrophy or through non-canonical dipeptide translation [15]. These observations, which followed those made for NOVA (neuro-oncological ventral antigen) [16] and SMA (spinal muscular atrophy) [17] proteins, have opened up the entire field of RBPs (RNA-binding proteins) and RNA metabolism as a new major area of research in neuroscience.

In the following sections we focus on the current knowledge of the TDP-43 RNA-binding mechanism and the characteristics of its interaction with other proteins in health and disease.

TDP-43–RNA interactions

Similar to most members of the hnRNP family, the main distinguishing feature of TDP-43 is its ability to bind RNA in a single-stranded and sequence-specific manner. This is achieved through two motifs that fold in a conserved 3D conformation, and are known as RRMs (RNA recognition motifs) (Figure 1A). In TDP-43, these regions are evolutionarily conserved throughout the animal kingdom, to the extent that its Drosophila melanogaster and Caenorhabditis elegans homologues can functionally substitute for the human protein (and vice versa) in a variety of experimental systems [1820]. Currently, there is scant detailed structural analysis of TDP-43 RRMs bound to RNA sequences, owing to the great intrinsic propensity of this protein to aggregate in solution and the consequent difficulty in crystallization and solution spectrometric measurements. At the present time, the only exceptions are the crystallographic structure of RRM2 bound to a small DNA molecule [21] and the functionally validated computer model of the RRM1 structure [19]. Nonetheless, it is clear from the biochemical characterization of TDP-43 that it has a high affinity for UG-repeated motifs, and that the RRM1 is necessary and sufficient for UG binding [3].

The RNA-binding function of TDP-43 is essential for most of the RNA-processing steps outlined in Figure 1. In particular, autoregulation is perhaps one of the most central to the field in neuropathies considering the sequestration of TDP-43 due to aggregation. The region responsible for this process is an extended binding region for TDP-43 called TDPBR (TDP-43-binding region) (Figure 1B) that was identified in the 3′-UTR of TDP-43 mRNA [4]. The TDPBR contains several non-UG sequences, which are essential for autoregulation of TDP-43 mRNA levels [22]. This observation, which was originally obtained in human cells in culture, were confirmed in a mouse transgenic for the human TDP-43 A315T mutant and by similar results in other transgenic mouse systems [2325].

The TDPBR sequences have been recently studied in detail with regard to their interaction with TDP-43 [26]. They have approximately 10-fold lower affinity than the GU repeats and some variability on the contact points within the TDP-43 surface was observed by biochemical approaches. The lower affinity is certainly a good characteristic for a sequence that acts as a sensor of TDP-43 concentration because a weaker interaction may favour recognition of different concentrations.

The self-regulation process has been extensively studied [4,22] and can be described briefly as follows. In the steady state of the cells with normal nuclear TDP-43 levels, the main TDP-43 mRNAs end in two polyadenylation sites (pA1 and pA4) located 1.37 kb and 2.8 kb within the extended 3′-UTR (Figure 1B) respectively. As pA4 is usually retained in the nucleus, most TDP-43 production within cells comes from the shorter transcript that uses pA1. In the case of an increased concentration of nuclear TDP-43, a normally silent intron in the 3′-UTR (intron 7) that contains the TDPBR and the pA1 sequences is spliced out (Figure 1C). This event forces the system to use a suboptimal splice site, pA2, and in addition there may be non-productive spliceosomal complexes formed that are usually followed by nuclear retention and rapid degradation of the mRNA [27]

This feedback loop in the cell is capable of keeping TDP-43 concentrations constant. In pathological conditions, however, formation of TDP-43 aggregates within the cell nucleus or cytoplasm will probably result in reduced free nuclear TDP-43, therefore the 3′-UTR TDPBR sensor will detect a fall in protein levels and respond with increased TDP-43 production. Such a situation would result in a vicious circle, increasing production and hence leading to larger aggregates, a total depletion of nuclear TDP-43 leading in turn to misregulation of cellular processes in which TDP-43 is involved, cell stress and death, even in the absence of direct toxic effects from TDP-43 aggregates.

TDP-43 protein–protein interactions

As with protein–RNA binding, most protein–protein interactions are determined by particular domains or sequences within the architecture of a protein. TDP-43 interacts with several proteins that modulate its RNA-processing functions, nuclear–cytoplasmic shuttling and its solubility. Among the most important binding partners, aside from itself (several lines of evidence suggest that TDP-43 may naturally occur as a dimer in solution) are several members of the hnRNP family, such as hnRNPA1 and hnRNPA2, hnRNPC and FUS/TLS which are necessary to mediate some of the biological properties of TDP-43 [2830] and are themselves directly involved in neurodegenerative diseases.

A fundamental characteristic of TDP-43 is its intrinsic propensity to aggregate [31,32]. It is now widely accepted that its C-terminal tail is responsible for most of its tendency to aggregate, even in the absence of particular cofactors or modifications, as demonstrated by physicochemical studies using synthetic peptides [33,34].

It was also initially noted that a glycine/asparagine-rich region in the TDP-43 C-terminal tail could disrupt endogenous TDP-43–hnRNPA2 complexes, and form high-molecular-mass complexes in vitro [30]. More recently it has become evident that the core sequence of this glycine/asparagine-rich region, corresponding to residues 342–366, is essential for TDP-43 self-interaction [35]. This region appears to be particularly important for the aggregation properties of TDP-43 as introducing repeated units of this sequence within cell lines or primary neuron cultures induces aggregate formation that recapitulates many of the characteristics of aggregates in patient cells [35]. It should also be noted, however, that TDP-43 protein–protein interactions are not limited to hnRNPs. In fact, proteomic studies performed on TDP-43 in several cell lines have detected a huge number of potential TDP-43-interacting partners. Some of these putative interactions have been at least partially studied, such as the ones with the Drosha complex, but many remain to be validated, especially at the functional level [36,37].

Regarding TDP-43 modifications that could promote aggregation, most attention has focused on the potential role of the CTFs (C-terminal fragments) that are observed in low amounts in the neurons of ALS and FTLD patients. Expression of CTFs of TDP-43 was shown to promote aggregation of TDP-43 in a considerable number of cell models [3840]. Nonetheless, TDP-43 aggregation is usually observed in neurons that express the wild-type protein. In addition, some TDP-43 mutations (identified predominantly in familial ALS cases and in the C-terminal sequence of the protein) have been shown to marginally enhance inclusion formation in a variety of experimental systems [32,4143]. Finally, introduction of mutations in the full-length TDP-43 that alter its nuclear localization signal or the nuclear export signal, not surprisingly, can cause both nuclear and cytoplasmic inclusions that are capable of sequestering wild-type endogenous TDP-43 [44]. In keeping with these results, TDP-43 aggregates have also been observed following knockdown of nuclear transport proteins such as karyopherin-β or the CAS (cellular apoptosis susceptibility) proteins, which results in increased cytoplasmic localization of TDP-43 [45].

Cellular processes involved in aggregation

Aside from TDP-43's natural ablity to aggregate, a series of other factors have also been noted to enhance aggregation, such as interaction with natural or synthetic polyglutamine protein aggregates such as those of ataxin-2 [46,47].

Key roles also seem to be played by the proteasome and autophagy systems [48,49]. In particular, TDP-43 aggregation is antagonized by overexpression of p62/SQSTM1 (sequestome 1) [50] and inhibition of USP14 (ubiquitin-specific peptidase 14) [51]. The involvement of these factors indicates a possibly crucial role of the autophagosome system in resolution of aggregates.

TDP-43 is recruited to SGs (stress granules) where it co-localizes with, binds to and controls the levels of several important factors implicated in SG formation and maintenance, such as G3BP {GTPase-activating protein [SH3 (Src homology 3) domain]-binding protein}, TIA-1 (T-cell-restricted intracellular antigen 1) and eIF4G (eukaryotic initiation factor 4G) [5256]. Therefore it is possible that prolonged stress could trigger aggregate formation of ‘pathological’ SGs [57]. In this respect, it has also been recently reported [58] that oxidative stress can lead to decreased TDP-43 solubility by oxidizing cysteine residues, which promotes the formation of intra- and inter-molecular disulfide crosslinks.

Taken together, these data suggest that TDP-43 is very promiscuous in terms of its interactions with RNA and proteins. For these reasons, the critical issue in this field is to identify the key interactions/cellular processes whose derangement(s) are primarily responsible for the phenomena observed in the brains of patients with neurodegenerative diseases.

As with many protein aggregation processes, it should be kept in mind that TDP-43 aggregation is a complex multi-step process that can be modified by many components, arising from both the internal and external environments. As a result, one of the major future challenges will be to determine the relative contribution to aggregate formation of each of these factors in order to identify the most likely targets for therapeutic intervention if resolution of the aggregates was shown to be beneficial for neural function.

Animal models

The biochemical studies performed on TDP-43 indicate that this protein plays a critical role in many aspects of a cell's life cycle. The importance of TDP-43 has been highlighted in many different transgenic animals, as recently reviewed by others [59]. Depending on how evolved the organism is, depletion or overexpression of TDP-43 has different effects.

For example, in depletion models in mammalian species, the absence of TDP-43 causes embryonic lethality. However, in less evolved animals with prolonged influence of maternal mRNAs from the egg, such as Drosophila melanogaster, depletion of TDP-43 may lead to reasonable normal development with some locomotion defects in the larva and a paralytic phenotype in the adult [20]. The paralysis is explained by atrophy of the neuromuscular junction that can be restored to its normal shape and branching pattern by pan-neuronal transgenic expression of either the Drosophila orthologue of TDP-43 (TBPH) or the human TDP-43 itself [10]. This observation is a dramatic example of function conservation through evolution in species as distant as humans and Drosophila.

In transgenic models with overexpression of TDP-43 the picture is more confusing, and it is likely that any alteration to the TDP-43 steady-state levels will enhance its natural propensity to aggregate, as it is now quite clear that excess of TDP-43 is toxic. As this is a very complex issue and environment and age will also certainly modulate this process, interested readers are directed to a specific review on the subject [60]

Taken together, these results emphasize the importance of further characterizing TDP-43 at a biochemical level and a better understanding of the processes controlled by it in the biology of the cells. In addition, it is essential to develop appropriate disease and aggregation model systems to test whether aggregation is protective, at least initially, or harmful. These models will provide the groundwork for devising potential novel therapeutic approaches for ALS and FTLD.

5th Conference on Advances in Molecular Mechanisms Underlying Neurological Disorders: A joint Biochemical Society/European Society for Neurochemistry Focused Meeting held at the University of Bath, U.K., 23–26 June 2013. Organized and Edited by Marcus Rattray (University of Bradford, U.K.) and Rob Williams (University of Bath, U.K.).

Abbreviations

     
  • ALS

    amyotrophic lateral sclerosis

  •  
  • CTF

    C-terminal fragment

  •  
  • FTLD

    frontotemporal lobar degeneration

  •  
  • FUS/TLS

    fused in sarcoma/translocated in liposarcoma

  •  
  • hnRNP

    heterogeneous nuclear ribonucleoprotein

  •  
  • RRM

    RNA recognition motif

  •  
  • SG

    stress granule

  •  
  • TDP-43

    TAR DNA-binding protein 43

  •  
  • TDPBR

    TDP-43-binding region

Funding

F.E.B. and E.B. are supported by grants from AriSLA (TARMA project) and Fondation Thierry Latran (REHNPALS) respectively.

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