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Source: the publisher, via Crossref · checked Oct 18, 2026 · Read the notice

TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets

Emma L. Scotter, Han-Jou Chen, Christopher E. Shaw

Neurotherapeutics · 2015 · Review · CC BY

doi:10.1007/s13311-015-0338-x

Abstract

Electronic supplementary material. The online version of this article (doi:10.1007/s13311-015-0338-x) contains supplementary material, which is available to authorized users.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease, and is characterized by the progressive loss of upper and lower motor neurons from the spinal cord, brain stem, and motor cortex, leading to muscle weakness and eventual respiratory failure. Approximately 5–10 % of ALS cases are familial with the remaining 90 % being sporadic, indicating that both genetic and environmental factors contribute to risk. Despite this diverse etiology of disease, 97 % of patients display a common phenotype in disease-affected tissues, namely the deposition of the TAR-DNA binding protein (TDP)-43. Deposition of TDP-43 is also the major feature of tau-negative frontotemporal dementia (FTD), which shows clinical overlap with ALS. This convergence of genetic and environmental risk factors upon TDP-43 is hugely informative with regard to general disease mechanisms. Here we explore the pathways linking risk factors to the development of TDP-43 proteinopathy, and linking proteinopathy to the development of disease, with a view to identifying key points for therapeutic intervention.

TDP-43 Protein Function

Encoded by TARDBP, TDP-43 is a ubiquitously expressed DNA-/RNA-binding protein. TDP-43 contains 2 RNA recognition motifs, a nuclear localization sequence (NLS), a nuclear export signal, and a glycine-rich C-terminus that mediates protein–protein interactions. TDP-43 predominantly resides in the nucleus, but is capable of nucleocytoplasmic shuttling. In the nucleus, TDP-43 plays a critical role in regulating RNA splicing, as well as modulating microRNA biogenesis. TDP-43 can regulate the stability of its own mRNA, providing a mechanism for the autoregulation of TDP-43 protein levels. In addition to TDP-43 RNA, TDP-43 regulates the splicing and stability of a large number of other transcripts, and thus influences diverse cellular processes.

Although mostly nuclear, up to ~30 % of TDP-43 protein can be found in the cytoplasm, with nuclear efflux regulated by both activity and stress. TDP-43 is a key component of dendritic and somatodendritic RNA transport granules in neurons, and plays an important role in neuronal plasticity by regulating local protein synthesis in dendrites. TDP-43 is also involved in the cytoplasmic stress granule response—the formation of protein complexes that sequester mRNAs redundant for survival—meaning TDP-43 function is particularly important under conditions of cellular stress. Understanding the functions of endogenous TDP-43 is crucial to establishing whether loss of these functions might be key to disease pathogenesis, and to developing effective therapeutics.

TDP-43 Proteinopathy

TDP-43 protein was identified as a major component of the ubiquitinated neuronal cytoplasmic inclusions deposited in cortical neurons in FTD and in spinal motor neurons in ALS. TDP-43-positive inclusions have subsequently been shown to be common to 97 % of ALS cases, whether sporadic or familial. The main exceptions are cases caused by mutations in SOD1 or FUS. Neurodegenerative diseases linked to the deposition of TDP-43 are termed “TDP-43 proteinopathies”, and “TDP-43 proteinopathy” also describes the characteristic histopathological transformation of TDP-43 that occurs in disease. This transformation is evidenced by the deposition of full-length and fragmented TDP-43 protein as detergent-resistant, ubiquitinated and hyperphosphorylated aggregates in the cytoplasm, with associated clearing of TDP-43 from the nucleus. The regional spread of TDP-43 proteinopathy from spinal and cortical motor neurons and glia to other cortical regions can be used to stage ALS progression, which suggests that some or all of the features of transformed TDP-43 protein are linked to pathogenesis.

However, a key question in ALS research is which of these features of TDP-43 proteinopathy are required for the development of disease and thus represent therapeutic targets. Is ALS pathogenesis linked to the loss of wild-type TDP-43 function through protein misfolding and failure to interact with binding partners, or is it linked to a gain of toxic function of the aforementioned TDP-43 aggregates, which are the hallmark of TDP-43 proteinopathy? A number of studies have examined the roles of TDP-43 gain or loss of function in disease. Overexpression of wild-type TDP-43 recapitulates TDP-43 proteinopathy and disease phenotypes in a range of animal models, supporting a role for gain of toxic function in disease. Initial studies testing a loss-of-function hypothesis used knock-out of TDP-43 from mice, which resulted in embryonic lethality. This demonstrated TDP-43 to play a vital role in early development without necessarily demonstrating that loss of function could be degenerative in adulthood. However, conditional and partial knockout models soon demonstrated that loss of TDP-43 function can, indeed, induce motor neuron defects, a progressive motor phenotype reminiscent of human disease, and even typical TDP-43 proteinopathy. Interestingly, either overexpression or knockdown of TDP-43 selectively in glia or muscle also recapitulates ALS-like phenotypes. The emerging picture is that both gain and loss of TDP-43 function may be mechanistic in disease, and, as we will demonstrate, TDP-43 misfolding may link the two. We will demonstrate that therapies that remedy TDP-43 misfolding should be prioritized to best target the spectrum of disease with the fewest assumptions around mechanism.

Disease Mechanisms Upstream of TDP-43 Proteinopathies

We have introduced the concept that TDP-43 is the convergence point for a range of upstream risk factors for ALS. Here we briefly review these genetic and environmental risk factors for the development of ALS, and for the development of TDP proteinopathy, and explore the potential for targeting therapeutics towards these diverse risk factors.

Genetic Factors in ALS

Currently, genetic causes are known for approximately 15 % of all ALS cases; accounting for 11 % of sporadic ALS and 68 % of familial ALS. Many of the ALS-linked genes group together functionally to implicate specific cellular processes in the pathogenesis of ALS (Table 1 and Fig. 1).

TARDBP mutations

Mutations in TARDBP are a rare cause of ALS. To date, 38 nonsynonymous TARDBP mutations have been identified in both familial and sporadic ALS, most clustering in the region encoding the C-terminus, and accounting for approximately 1–2 % of total cases. Like wild-type TDP-43 proteinopathy, mutant TDP-43 in TARDBP-linked ALS patient tissue is characterized by cytoplasmic accumulation as aggregated and insoluble deposits, nuclear clearing in a subset of motor neurons, and C-terminal fragmentation. But what is the relationship of mutant TDP-43 proteinopathy to pathogenesis?

Cellular and transgenic animal models indicate that both overt proteinopathy, as well as preproteinopathic changes in TDP-43 may be at play in TARDBP-linked disease. Loss of RNA processing and axonal transport function of mutant TDP-43 has been suggested to precede other features of pathology, and the failure of mutant TDP-43 to rescue motor neuron defects caused by knockout of endogenous TDP-43 supports the notion that TARDBP mutations cause loss of function. However, they also promote C-terminal fragmentation, cytoplasmic mislocalization, aggregation, and altered proteostasis. These structural abnormalities may therefore underpin both loss of function and proteinopathic transformation of mutant TDP-43. The fact that TARDBP mutations cause ALS provides robust evidence that altered TDP-43 structure (i.e., misfolding) and the resultant loss and gain of function is not simply a cellular response to disease but is pathogenic.

We previously demonstrated that a mutant TDP-43 allele (M337V) can be selectively silenced using small interfering RNA, and, indeed, mutation-specific therapy may become feasible with the recent demonstration of safety of silencing agents in humans. However, generic TDP-43-based refolding or reduction strategies to be discussed ahead in this review may be more broadly useful, given the number of unique TARDBP mutations linked to disease.

Protein degradation gene mutations

ALS-linked mutations in SQSTM1, VCP, UBQLN2, and OPTN are rare but together implicate impaired protein turnover in TDP-43 proteinopathy and in ALS pathogenesis. They encode p62, valosin-containing protein (VCP), ubiquilin 2, and optineurin, repectively; effectors of the autophagy and/or ubiquitin-proteasome system (UPS) protein degradation pathways. TDP-43 proteostasis is normally maintained by the coordinated action of the UPS and authophagy, which is particularly important for clearing TDP-43 oligomers and aggregates.

Notably, VCP and p62 are required for the formation of “aggresomes”, which are large perinuclear inclusions decorated with ubiquitin, ubiquilin, and p62. The TDP-43-positive aggregates that are the hallmark ALS pathology are likely aggresomes. Aggresomes act as a staging center for “aggrephagy”—the removal of misfolded proteins by autophagy—and augmentation of aggrephagy is thus emerging as a potential therapeutic strategy in ALS.

But is the removal of TDP-43 a logical approach in ALS linked to global impairment of protein degradation, when TDP-43 is just one of many substrates of these systems? At the high concentrations caused by global impairment in protein degradation, TDP-43, like other neurodegenerative disease proteins, and RNA-binding proteins (RBPs), is highly prone to aggregation. Thus, TDP-43 may be particularly adversely affected by genetic mutations affecting protein homeostasis. Supporting this idea, the predominant pathology in ALS linked to VCP mutation is the nuclear accumulation of TDP-43 rather than VCP protein itself or other degradation substrates. Therefore, it is feasible that the misfolding and accumulation of TDP-43 and not other proteins is the “smoking gun”, and clearance of misfolded TDP-43 might represent a common druggable target.

Certainly, small molecule activators of the UPS or autophagy have been shown to promote TDP-43 clearance and/or mitigate toxicity in models based on TDP-43 overexpression. Autophagy activators may offer selectivity in clearing misfolded TDP-43; however, given the ability of TDP-43 to autoregulate, even nonselective clearance strategies hold promise for safely restoring TDP-43 proteostasis.

RNA processing pathway gene mutations

The identification of disease-linked mutations affecting other RNA-binding proteins suggests an important role for deficits in RNA processing, which is a key TDP-43 function, in disease pathogenesis. ALS-linked mutations in the RBP fused in sacroma (FUS) lead to its mislocalization from the nucleus to the cytoplasm and aggregation, but they do not cause TDP-43 proteinopathy. However, TDP-43 and FUS do share a subset of RNA targets, which may be part of a disease-relevant pathway. Indeed, RNA targets shared with TDP-43 may also be involved in ALS linked to other RNA processing genes.

The most common ALS-linked mutation is an intronic GGGGCC repeat expansion in C9ORF72, the pathology of which is characterized by classical TDP-43 inclusions in the motor cortex and spinal cord. C9ORF72-linked disease can be distinguished by the additional presence of nuclear foci of repeat-containing RNA. These RNA foci sequester RBPs, leading to dysregulation of a large number of transcripts. C9ORF72 cases also harbor TDP-43-negative inclusions throughout the central nervous system, which are decorated by ubiquitin, p62, and/ or ubiquilin 2. These inclusions contain dipeptide-repeat proteins (DPRs) translated in all 6 frames from repeat-containing RNA. Overexpression of DPRs, particularly those that are arginine-rich (polyGR, polyPR), can cause toxicity independently of RNA foci formation. However, the distribution of dipeptide aggregates in ALS/FTD brain and spinal cord, at least for polyGA, shows poor correlation with neurodegeneration. Mapping of arginine-rich DPRs, including preaggregated species, may reveal a role for DPRs in disease, but currently the marker most closely correlated with degeneration remains TDP-43 deposition. Thus, while the reduction of repeat-containing transcript levels or foci formation holds promise in C9ORF72-mediated disease, TDP-43 misfolding should also be pursued as a potential therapeutic target.

Mutations in the RNA-binding protein genes MATR3 and hnRNPA1 are also associated with ALS and TDP-43 proteinopathy, potentially through direct binding of the affected RBP to TDP-43. Taken together with FUS and C9ORF72, these ALS-linked genes indicate that RNA processing deficits can be a cause of ALS in the presence or absence of TDP-43 proteinopathy, and that rescue of RNA processing defects could be beneficial to patients. As is the case for C9ORF72-linked disease, the extent to which RNA processing defects are due to TDP-43 proteinopathy will determine whether TDP-43-based therapeutics are effective in patients.

Environmental Stress

For the majority of ALS cases, no genetic mutations have yet been identified to account for disease; therefore, the development of ALS and TDP-43 proteinopathy in susceptible individuals is thought to also involve environmental factors. This idea was first proposed following observations of unexpectedly high disease incidence rates in certain “hotspots”, such as the Kii peninsula of Japan and the island of Guam. While patients in these regions show an increased frequency of ALS-linked genes or genetic modifiers such as MAPT, these only partly account for the observed rates of disease. Proposed environmental agents underlying the high incidence in these populations include dietary neurotoxins such as β-methylamino-L-alanine, or mineral deficiencies.

There is an association between US military service and increased risk of ALS, which may implicate intense physical activity, or exposure to lead, pesticides, or other toxins. Exposure to electromagnetic fields, agricultural chemicals, head injuries, and smoking may also increase susceptibility. Increased incidence of ALS has been reported in professional football players; however, this link has been disputed, and risk is not increased for other professional athletes. While no single environmental factor has been unequivocally linked to increased ALS risk, the risk factors discussed can collectively be viewed as cellular stressors, and together implicate cellular stress in disease pathogenesis.

Indeed, cellular studies have drawn links between a diverse range of stressors and the properties of TDP-43 protein. Osmotic stress, oxidative stress, endoplasmic reticulum stress, and heat stress can induce TDP-43 to redistribute from the nucleus to the cytoplasm and incorporate into stress granules. While the regulated aggregation of RBPs and RNA into stress granules is wholly reversible under normal conditions, it has been proposed that in conditions of prolonged or repeated neuronal stress, stress granules might act to “seed” the irreversible pathological transformation of TDP-43. Certainly, TDP-43 within stress granules is detergent resistant and may become post-translationally modified, which are defining features of TDP-43 proteinopathy. Also, stress granule markers have been found by several groups to co-localize with TDP-43 aggregates in ALS patient spinal cord, although not by others. Together, these findings suggest that myriad and diverse environmental stressors, which normally induce the reversible coalescence of TDP-43 into stress granules, might instead promote irreversible TDP-43 changes and that these are linked to a common pattern of degeneration. A number of antioxidants have been trialed in patients with ALS, unfortunately without success, highlighting the need for better understanding of factors which precipitate proteinopathy and disease.

Disease Mechanisms via TDP-43 Proteinopathy: Toxic Features and Points of Intervention

The vast majority of ALS and FTD cases are of unknown etiology but are linked by TDP-43 proteinopathy, which is defined by cytoplasmic mislocalization, fragmentation, aggregation, and post-translational modification. Here we examine how each of these features of pathological TDP-43 is linked to ALS pathogenesis, and whether preventing these common features might be a valid therapeutic strategy.

Cytoplasmic Mislocalization of TDP-43

Mislocalization of TDP-43 in ALS and FTD is evidenced by the deposition of granular, skein-like, and macroaggregated TDP-43 in the cytoplasm, as well as clearing of TDP-43 from the nucleus. Enhanced levels of TDP-43 in the cytoplasm can occur downstream of ALS-linked mutations, cellular stress, or impaired degradation. TDP-43 mislocalization can be induced in model systems by targeted mutation of the NLS; importantly, this sets in motion many pathological features of disease—NLS mutant TDP-43 is cytoplasmic, aggregated, and capable of recruiting wild-type TDP-43. Interestingly, several studies have shown that increased levels of cytoplasmic TDP-43 are toxic to cells, but that toxicity is independent of inclusion formation at the level of light microscopy. An important question therefore is whether pathogenic TDP-43 in the cytoplasm is natively folded or misfolded.

As a very early pathogenic event cytoplasmic mislocalization is a desirable intervention point, and selectively reducing mislocalized TDP-43 is linked to reduced toxicity in vivo. However, studies that demonstrated that link had targeted autophagy or interactions with stress granule components rather than TDP-43 nucleocytoplasmic shuttling per se. Without identifying the unique characteristics of the subset of cytoplasmic TDP-43 that exerts toxicity, developing therapeutics that do not affect TDP-43 undergoing normal nucleocytoplasmic shuttling may be challenging.

Fragmentation of TDP-43

Phosphorylated C-terminal fragments (CTFs) of TDP-43 are a major constituent of neuronal protein inclusions in ALS and FTD brains, but less so in spinal cord. Cleavage of TDP-43 is enhanced by C-terminal TDP-43 mutations, by cellular stress, and proteasomal inhibition. Cleavage generates CTFs, which mislocalize to the cytoplasm owing to removal of the NLS, and are aggregation-prone owing to the presence of a prion-like domain. CTFs that correspond in size to those in ALS patient tissue may “seed” the formation of inclusions that are detergent-resistant and ubiquitinated, and able to sequester full-length TDP-43.

But is fragmentation of TDP-43 a target for therapeutic intervention? There is no current consensus as to whether cleavage enhances or mitigates TDP-43 toxicity. It has been proposed that TDP-43 toxicity requires intact RNA binding capacity; therefore, CTFs may not directly exert toxicity. Cleavage is also not a prerequisite for TDP-43 aggregation; indeed, CTFs expressed at physiological levels require a second “hit” to precipitate misfolding and aggregation. Importantly, cleavage may be required for normal TDP-43 degradation, such that preventing cleavage would favor the accumulation of TDP-43, possibly to greater detriment. Current evidence therefore argues that inhibiting fragmentation of TDP-43 may not be a sound approach for preventing ALS pathogenesis.

Misfolding, Aggregation, and Insolubility of TDP-43

The role of TDP-43 aggregation in pathogenesis is one of the most controversial topics in ALS research; thus, preventing aggregation as a therapeutic strategy is equally controversial. Several animal studies have found that mutant TDP-43 causes toxicity in the absence of visible aggregates, and preventing visible TDP-43 aggregates from forming failed to reduce toxicity in a cellular model. It should be noted, however, that visible aggregates are only the endpoint of an aggregation pathway that includes a range of TDP-43 species from misfolded monomer to oligomer to mature aggregate. Unfortunately, sensitive methods for detecting misfolded or early aggregated isoforms are seldom employed, so it is difficult to rule out their existence in studies that fail to find aggregates by light microscopy. Certainly, the vast majority of ALS-linked TDP-43 mutations are found in the prion-like C-terminal domain and serve to promote misfolding, which strongly implies that disease pathogenesis is linked, if not to visible inclusions then at least to TDP-43 misfolding.

Misfolded mutant TDP-43 shows a reduced ability to transport RNA appropriately, constituting a loss of function. Subsequent to misfolding, the formation of oligomers and aggregates of TDP-43 in the cytoplasm may recruit native TDP-43 or its interactors. This constitutes a gain of function, which acts in a dominant-negative fashion, thus essentially also causing loss of function. By restoring proper TDP-43 folding and/or clearing early misfolded TDP-43, we predict that both loss and gain of function toxicity could be abrogated. It is also possible that late TDP-43 aggregates acquire novel toxic functions such as impairment of the proteasome or blockade of axonal transport, but few studies have addressed this. If large aggregates are not a toxic species then strategies that prevent the sequestration of toxic misfolded species into macroaggregates might be detrimental.

There are several intrinsic cellular mechanisms that can act to either prevent or resolve protein misfolding, namely the chaperone system, autophagy, and the UPS. The chaperone system maintains proper protein folding during synthesis and thereafter, or delivers misfolded substrates for degradation. In the case of TDP-43, the chaperone heat shock protein (Hsp)90 enhances solubility (i.e., folding), while HspB8 promotes autophagic clearance of aggregated TDP-43. Potentiated forms of the disaggregase Hsp104 can mediate TDP-43 refolding. Monomeric misfolded TDP-43 is likely handled by the UPS.

Augmentation of chaperones or protein degradation pathways has been protective in several models of ALS and FTD. Because TDP-43 misfolding causes loss of function, as well as providing a substrate for aggregation and gain-of-function/dominant-negative toxicity, we see early misfolding events as one of the most attractive therapeutic targets in ALS with TDP-43 proteinopathy.

Phosphorylation and Ubiquitination of TDP-43

In ALS and FTD patient tissue, hyperphosphorylation and ubiquitination are signatures for pathological TDP-43, as they preferentially label TDP-43 that is cleaved, aggregated, and detergent-resistant. Phosphorylation appears to precede ubiquitination, and phospho-TDP-43-specific antibodies detect a greater proportion of TDP-43 inclusions in patient tissue. However, the role of post-translational modifications in promoting or preventing TDP-43 toxicity, and the likely therapeutic benefit of targeting them, remains hotly debated.

There are 29 phosphorylation sites on TDP-43 for casein kinase 1 alone, the best studied of which are residues 409/410. Casein kinase 2 may also phosphorylate TDP-43. TDP-43 phosphorylation at 409/410 is not a prerequisite for aggregation. However, when phosphorylation is detected it is almost always associated with misfolding and insolubility of TDP-43. In addition, interventions that modify TDP-43 phosphorylation have been demonstrated to alter its toxicity. Unfortunately, the reported studies conflict over whether TDP-43 phosphorylation mitigates or exacerbates aggregation and toxicity. Thus, at present, TDP-43 phosphorylation is of uncertain value as a therapeutic target but can be considered a good marker for gauging the efficacy of therapeutics that aim to modify TDP-43 misfolding.

The influence of ubiquitination on TDP-43 proteinopathy is less well studied. TDP-43 is modified with polyubiquitin chains that are predominantly K48- or K63-linked. However, it is unclear precisely which TDP-43 conformers are ubiquitinated, and what the effects of TDP-43 ubiquitination are. Ubiquitination involving UBE2E ubiquitin ligases causes TDP-43 to shift to the insoluble fraction, but does not promote its degradation. In contrast, Parkin ubiquitination of TDP-43 promotes its cytosolic translocation either with or without an enhancement in degradation. Studies preventing the removal of ubiquitin chains have yielded conflicting answers as to the possible therapeutic utility of targeting TDP-43 ubiquitination. Inhibition of the deubiquitinase USP14 promotes TDP-43 clearance through retention of ubiquitin chains. However, knockdown of the deubiquitinase UBPY exacerbated the toxicity of TDP-43 in Drosophila, despite ubiquitin chain retention. The promiscuity of deubiquitinases may limit the therapeutic usefulness of inhibitors in patients; however, augmentation of proteolysis itself, which declines with age, remains a potential strategy in ALS, as well as other neurodegenerative diseases.

Conclusions and Future Perspectives

The contributions of genetic and environmental factors to the etiology of ALS and FTD are complex and interwoven. The increasing accessibility of genotyping and the recent demonstration of safe gene silencing using antisense oligonucleotides may render the targeting of individual gene mutations feasible, but currently this is not the case, except perhaps for C9ORF72 patients. Similarly, dysregulated RNA processing almost certainly lies at the heart of pathogenesis, but its widespread downstream effects argue against rescue of selected transcripts being useful in patients. Therapeutic strategies would best be directed at a common target proximal to the deficit, which, for most cases, is the misfolding of TDP-43 that is central to its loss of function and gain of function/dominant-negative toxicity. Specifically, enhancers of chaperone-dependent TDP-43 folding, as well as activators of the UPS and autophagy, have shown most promise in model systems. Ongoing refinement of model systems in which to test therapeutics, and recognition of the roles of non-neuronal cell types will be important in bringing these compounds to preclinical and clinical testing. In addition, unbiased large-scale compound screening efforts and the identification of novel causative genes may yield additional insights into disease mechanisms and the role of TDP-43.

Below is the link to the electronic supplementary material.

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    Not in our library10.1002/ana.23937

  31. 31.

    Wils H, Kleinberger G, Janssens J, et al. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A. 2010;107:3858-3863.

    Not in our library10.1073/pnas.0912417107

  32. 32.

    Li Y, Ray P, Rao EJ, et al. A Drosophila model for TDP-43 proteinopathy. Proc Natl Acad Sci U S A. 2010;107:3169-3174.

    Not in our library10.1073/pnas.0913602107

  33. 33.

    Ash PE, Zhang YJ, Roberts CM, et al. Neurotoxic effects of TDP-43 overexpression in C. elegans. Hum Mol Genet. 2010;19:3206-3218.

    Not in our library10.1093/hmg/ddq230

  34. 34.

    Wu LS, Cheng WC, Hou SC, Yan YT, Jiang ST, Shen CK. TDP-43, a neuro-pathosignature factor, is essential for early mouse embryogenesis. Genesis. 2010;48:56-62.

    Not in our library10.1002/dvg.20584

  35. 35.

    Sephton CF, Good SK, Atkin S, et al. TDP-43 is a developmentally regulated protein essential for early embryonic development. J Biol Chem. 2010;285:6826-6834.

    Not in our library10.1074/jbc.m109.061846

  36. 36.

    Kraemer BC, Schuck T, Wheeler JM, et al. Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol. 2010;119:409-419.

    Not in our library10.1007/s00401-010-0659-0

  37. 37.

    Wu LS, Cheng WC, Shen CK. Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice. J Biol Chem. 2012;287:27335-27344.

    Not in our library10.1074/jbc.m112.359000

  38. 38.

    Iguchi Y, Katsuno M, Niwa J, et al. Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain. 2013;136:1371-1382.

    Not in our library10.1093/brain/awt029

  39. 39.

    Kabashi E, Lin L, Tradewell ML, et al. Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo. Hum Mol Genet. 2010;19:671-683.

    Not in our library10.1093/hmg/ddp534

  40. 40.

    Yang C, Wang H, Qiao T, et al. Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2014;111:E1121-E1129.

    Not in our library10.1073/pnas.1322641111

  41. 41.

    Diaper DC, Adachi Y, Lazarou L, et al. Drosophila TDP-43 dysfunction in glia and muscle cells cause cytological and behavioural phenotypes that characterize ALS and FTLD. Hum Mol Genet. 2013;22:3883-3893.

    Not in our library10.1093/hmg/ddt243

  42. 42.

    Renton AE, Chio A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci. 2014;17:17-23.

    Not in our library10.1038/nn.3584

  43. 43.

    Sreedharan J, Blair IP, Tripathi VB, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008;319:1668-1672.

    Not in our library10.1126/science.1154584

  44. 44.

    Van Deerlin VM, Leverenz JB, Bekris LM, et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008;7:409-416.

    Not in our library10.1016/s1474-4422(08)70071-1

  45. 45.
    Novel Mutations in TARDBP (TDP-43) in Patients with Familial Amyotrophic Lateral Sclerosis · 2008
    No notice
  46. 46.

    Kabashi E, Valdmanis PN, Dion P, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008;40:572-574.

    Not in our library10.1038/ng.132

  47. 47.

    Abel O, Powell JF, Andersen PM, Al-Chalabi A. ALSoD: A user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics. Hum Mutat. 2012;33:1345-1351.

    Not in our library10.1002/humu.22157

  48. 48.

    Corrado L, Ratti A, Gellera C, et al. High frequency of TARDBP gene mutations in Italian patients with amyotrophic lateral sclerosis. Hum Mutat. 2009;30:688-694.

    Not in our library10.1002/humu.20950

  49. 49.

    Kirby J, Goodall EF, Smith W, et al. Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis. Neurogenetics. 2010;11:217-225.

    Not in our library10.1007/s10048-009-0218-9

  50. 50.
    Association between novel TARDBP mutations and Chinese patients with amyotrophic lateral sclerosis · 2010
    Not checked
  51. 51.

    Zou ZY, Peng Y, Wang XN, Liu MS, Li XG, Cui LY. Screening of the TARDBP gene in familial and sporadic amyotrophic lateral sclerosis patients of Chinese origin. Neurobiol Aging. 2012;33:2229 e11-e18.

    Not in our library10.1016/j.neurobiolaging.2012.03.014

  52. 52.

    Del Bo R, Ghezzi S, Corti S, et al. TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations. Eur J Neurol. 2009;16:727-732.

    Not in our library10.1111/j.1468-1331.2009.02574.x

  53. 53.

    Lemmens R, Race V, Hersmus N, et al. TDP-43 M311V mutation in familial amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2009;80:354-355.

    Not in our library10.1136/jnnp.2008.157677

  54. 54.

    Baumer D, Parkinson N, Talbot K. TARDBP in amyotrophic lateral sclerosis: identification of a novel variant but absence of copy number variation. J Neurol Neurosurg Psychiatry. 2009;80:1283-1285.

    Not in our library10.1136/jnnp.2008.166512

  55. 55.

    Yokoseki A, Shiga A, Tan CF, et al. TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol. 2008;63:538-542.

    Not in our library10.1002/ana.21392

  56. 56.

    Kuhnlein P, Sperfeld AD, Vanmassenhove B, et al. Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations. Arch Neurol. 2008;65:1185-1189.

    Not in our library10.1001/archneur.65.9.1185

  57. 57.

    Daoud H, Valdmanis PN, Kabashi E, et al. Contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis. J Med Genet. 2009;46:112-114.

    Not in our library10.1136/jmg.2008.062463

  58. 58.

    Origone P, Caponnetto C, Bandettini Di Poggio M, et al. Enlarging clinical spectrum of FALS with TARDBP gene mutations: S393L variant in an Italian family showing phenotypic variability and relevance for genetic counselling. Amyotroph Lateral Scler. 2010;11:223-227.

    Not in our library10.3109/17482960903165039

  59. 59.

    Arnold ES, Ling SC, Huelga SC, et al. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc Natl Acad Sci U S A. 2013;110:E736-E745.

    Not in our library10.1073/pnas.1222809110

  60. 60.

    Bilican B, Serio A, Barmada SJ, et al. Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc Natl Acad Sci U S A. 2012;109:5803-5808.

    Not in our library10.1073/pnas.1202922109

  61. 61.

    Serio A, Bilican B, Barmada SJ, et al. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proc Natl Acad Sci U S A. 2013;110:4697-4702.

    Not in our library10.1073/pnas.1300398110

  62. 62.

    Han JH, Yu TH, Ryu HH, et al. ALS/FTLD-linked TDP-43 regulates neurite morphology and cell survival in differentiated neurons. Exp Cell Res. 2013;319:1998-2005.

    Not in our library10.1016/j.yexcr.2013.05.025

  63. 63.

    Nonaka T, Kametani F, Arai T, Akiyama H, Hasegawa M. Truncation and pathogenic mutations facilitate the formation of intracellular aggregates of TDP-43. Hum Mol Genet. 2009;18:3353-3364.

    Not in our library10.1093/hmg/ddp275

  64. 64.

    Johnson BS, Snead D, Lee JJ, McCaffery JM, Shorter J, Gitler AD. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J Biol Chem. 2009;284:20329-20339.

    Not in our library10.1074/jbc.m109.010264

  65. 65.

    Budini M, Romano V, Avendano-Vazquez SE, Bembich S, Buratti E, Baralle FE. Role of selected mutations in the Q/N rich region of TDP-43 in EGFP-12xQ/N-induced aggregate formation. Brain Res. 2012;1462:139-150.

    Not in our library10.1016/j.brainres.2012.02.031

  66. 66.

    Barmada SJ, Serio A, Arjun A, et al. Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol. 2014;10:677-685.

    Not in our library10.1038/nchembio.1563

  67. 67.

    Ling SC, Albuquerque CP, Han JS, et al. ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc Natl Acad Sci U S A. 2010;107:13318-13323.

    Not in our library10.1073/pnas.1008227107

  68. 68.

    Watanabe S, Kaneko K, Yamanaka K. Accelerated disease onset with stabilized familial amyotrophic lateral sclerosis (ALS)-linked mutant TDP-43 proteins. J Biol Chem. 2013;288:3641-3654.

    Not in our library10.1074/jbc.m112.433615

  69. 69.

    Wu LS, Cheng WC, Shen CK. Similar dose-dependence of motor neuron cell death caused by wild type human TDP-43 and mutants with ALS-associated amino acid substitutions. J Biomed Sci. 2013;20:33.

    Not in our library10.1186/1423-0127-20-33

  70. 70.

    Nishimura AL, Shum C, Scotter EL, et al. Allele-specific knockdown of ALS-associated mutant TDP-43 in neural stem cells derived from induced pluripotent stem cells. PLoS One. 2014;9:e91269.

    Not in our library10.1371/journal.pone.0091269

  71. 71.

    Miller TM, Pestronk A, David W, et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 2013;12:435-442.

    Not in our library10.1016/s1474-4422(13)70061-9

  72. 72.

    Fecto F, Yan J, Vemula SP, et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol. 2012;68:1440-1446.

    Not in our library10.1001/archneurol.2011.250

  73. 73.

    Watts GD, Wymer J, Kovach MJ, et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet. 2004;36:377-381.

    Not in our library10.1038/ng1332

  74. 74.

    Deng HX, Chen W, Hong ST, et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011;477:211-215.

    Not in our library10.1038/nature10353

  75. 75.

    Maruyama H, Morino H, Ito H, et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature. 2010;465:223-226.

    Not in our library10.1038/nature08971

  76. 76.

    Ju JS, Fuentealba RA, Miller SE, et al. Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol. 2009;187:875-888.

    Not in our library10.1083/jcb.200908115

  77. 77.

    Tresse E, Salomons FA, Vesa J, et al. VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. Autophagy. 2010;6:217-227.

    Not in our library10.4161/auto.6.2.11014

  78. 78.

    Seibenhener ML, Babu JR, Geetha T, Wong HC, Krishna NR, Wooten MW. Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol. 2004;24:8055-8068.

    Not in our library10.1128/mcb.24.18.8055-8068.2004

  79. 79.

    Pankiv S, Clausen TH, Lamark T, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007;282:24131-24145.

    Not in our library10.1074/jbc.m702824200

  80. 80.

    Kleijnen MF, Shih AH, Zhou P, et al. The hPLIC Proteins may provide a link between the ubiquitination machinery and the proteasome. Mol Cell. 2000;6:409-419.

    Not in our library10.1016/s1097-2765(00)00040-x

  81. 81.

    N'Diaye EN, Kajihara KK, Hsieh I, Morisaki H, Debnath J, Brown EJ. PLIC proteins or ubiquilins regulate autophagy-dependent cell survival during nutrient starvation. EMBO Rep. 2009;10:173-179.

    Not in our library10.1038/embor.2008.238

  82. 82.

    Wild P, Farhan H, McEwan DG, et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science. 2011;333:228-233.

    Not in our library10.1126/science.1205405

  83. 83.
    Differential roles of the ubiquitin proteasome system (UPS) and autophagy in the clearance of soluble and aggregated TDP-43 species · 2014
    No notice
  84. 84.

    Caccamo A, Majumder S, Deng JJ, Bai Y, Thornton FB, Oddo S. Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability. J Biol Chem. 2009;284:27416-27424.

    Not in our library10.1074/jbc.m109.031278

  85. 85.

    Urushitani M, Sato T, Bamba H, Hisa Y, Tooyama I. Synergistic effect between proteasome and autophagosome in the clearance of polyubiquitinated TDP-43. J Neurosci Res. 2010;88:784-797.

    Not in our library10.1002/jnr.22243

  86. 86.

    Wang X, Fan H, Ying Z, Li B, Wang H, Wang G. Degradation of TDP-43 and its pathogenic form by autophagy and the ubiquitin-proteasome system. Neurosci Lett. 2010;469:112-116.

    Not in our library10.1016/j.neulet.2009.11.055

  87. 87.

    Zhang YJ, Xu YF, Cook C, et al. Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci U S A. 2009;106:7607-7612.

    Not in our library10.1073/pnas.0900688106

  88. 88.

    Wojcik C, Yano M, DeMartino GN. RNA interference of valosin-containing protein (VCP/p97) reveals multiple cellular roles linked to ubiquitin/proteasome-dependent proteolysis. J Cell Sci. 2004;117:281-292.

    Not in our library10.1242/jcs.00841

  89. 89.

    Lamark T, Johansen T. Autophagy: links with the proteasome. Curr Opin Cell Biol. 2009;22:192-198.

    Not in our library10.1016/j.ceb.2009.11.002

  90. 90.

    Thomas M, Alegre-Abarrategui J, Wade-Martins R. RNA dysfunction and aggrephagy at the centre of an amyotrophic lateral sclerosis/frontotemporal dementia disease continuum. Brain. 2013;136:1345-1360.

    Not in our library10.1093/brain/awt030

  91. 91.
    Aggrephagy: Selective Disposal of Protein Aggregates by Macroautophagy · 2012
    No notice
  92. 92.

    Kopito RR. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 2000;10:524-530.

    Not in our library10.1016/s0962-8924(00)01852-3

  93. 93.

    Colby DW, Cassady JP, Lin GC, Ingram VM, Wittrup KD. Stochastic kinetics of intracellular huntingtin aggregate formation. Nat Chem Biol. 2006;2:319-323.

    Not in our library10.1038/nchembio792

  94. 94.

    Jarrett JT, Lansbury PT. Seeding "one-dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell. 1993;73:1055-1058.

    Not in our library10.1016/0092-8674(93)90635-4

  95. 95.

    Wood SJ, Wypych J, Steavenson S, Louis J-C, Citron M, Biere AL. α-Synuclein fibrillogenesis is nucleation-dependent: Implications for the pathogenesis of Parkinsonatidisease. J Biol Chem. 1999;274:19509-19512.

    Not in our library10.1074/jbc.274.28.19509

  96. 96.

    King OD, Gitler AD, Shorter J. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res. 2012;1462:61-80.

    Not in our library10.1016/j.brainres.2012.01.016

  97. 97.

    Johnson JO, Mandrioli J, Benatar M, et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron. 2010;68:857-864.

    Not in our library10.1016/j.neuron.2010.11.036

  98. 98.

    Lee BH, Lee MJ, Park S, et al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature. 2010;467:179-184.

    Not in our library10.1038/nature09299

  99. 99.

    Wang IF, Guo BS, Liu YC, et al. Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc Natl Acad Sci U S A. 2012;109:15024-15029.

    Not in our library10.1073/pnas.1206362109

  100. 100.

    Lagier-Tourenne C, Polymenidou M, Hutt KR, et al. Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci. 2012;15:1488-1497.

    Not in our library10.1038/nn.3230

  101. 101.

    Honda D, Ishigaki S, Iguchi Y, et al. The ALS/FTLD-related RNA-binding proteins TDP-43 and FUS have common downstream RNA targets in cortical neurons. FEBS Open Bio. 2013;4:1-10.

    Not in our library10.1016/j.fob.2013.11.001

  102. 102.

    DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72:245-256.

    Not in our library10.1016/j.neuron.2011.09.011

  103. 103.

    Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72:257-268.

    Not in our library10.1016/j.neuron.2011.09.010

  104. 104.
    Hexanucleotide Repeats in ALS/FTD Form Length-Dependent RNA Foci, Sequester RNA Binding Proteins, and Are Neurotoxic · 2013
    Not checked
  105. 105.
    Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions · 2014
    No notice
  106. 106.

    Lagier-Tourenne C, Baughn M, Rigo F, et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A. 2013;110:E4530-E4539.

    Not in our library10.1073/pnas.1318835110

  107. 107.

    Donnelly CJ, Zhang PW, Pham JT, et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron. 2013;80:415-428.

    Not in our library10.1016/j.neuron.2013.10.015

  108. 108.

    Troakes C, Maekawa S, Wijesekera L, et al. An MND/ALS phenotype associated with C9orf72 repeat expansion: abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline. Neuropathology. 2012;32:505-514.

    Not in our library10.1111/j.1440-1789.2011.01286.x

  109. 109.

    Brettschneider J, Van Deerlin VM, Robinson JL, et al. Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol. 2012;123:825-839.

    Not in our library10.1007/s00401-012-0970-z

  110. 110.
    Dipeptide repeat proteins are present in the p62 positive inclusions in patients with frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72 · 2013
    No notice
  111. 111.

    Ash PE, Bieniek KF, Gendron TF, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron. 2013;77:639-646.

    Not in our library10.1016/j.neuron.2013.02.004

  112. 112.

    Mori K, Weng SM, Arzberger T, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. 2013;339:1335-1338.

    Not in our library10.1126/science.1232927

  113. 113.

    Kwon I, Xiang S, Kato M, et al. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science. 2014;345:1139-1145.

    Not in our library10.1126/science.1254917

  114. 114.

    Mizielinska S, Gronke S, Niccoli T, et al. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science. 2014;345:1192-1194.

    Not in our library10.1126/science.1256800

  115. 115.

    Yamakawa M, Ito D, Honda T, et al. Characterization of the dipeptide repeat protein in the molecular pathogenesis of c9FTD/ALS. Hum Mol Genet 2014 Nov 14 [Epub ahead of print].

    Not in our library10.1093/hmg/ddu576

  116. 116.
    C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration · 2014
    No notice
  117. 117.

    Davidson YS, Barker H, Robinson AC, et al. Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72. Acta Neuropathol Commun. 2014;2:70.

    Not in our library10.1186/2051-5960-2-70

  118. 118.

    Mackenzie IR, Arzberger T, Kremmer E, et al. Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol. 2013;126:859-879.

    Not in our library10.1007/s00401-013-1181-y

  119. 119.

    Su Z, Zhang Y, Gendron TF, et al. Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron. 2014;83:1043-1050.

    Not in our library10.1016/j.neuron.2014.07.041

  120. 120.

    Zamiri B, Reddy K, Macgregor RB, Pearson CE. TMPyP4 porphyrin distorts RNA G-quadruplex structures of the disease-associated r(GGGGCC)n repeat of the C9orf72 gene and blocks interaction of RNA-binding proteins. J Biol Chem. 2014;289:4653-4659.

    Not in our library10.1074/jbc.c113.502336

  121. 121.

    Johnson JO, Pioro EP, Boehringer A, et al. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat Neurosci. 2014;17:664-666.

    Not in our library10.1038/nn.3688

  122. 122.

    Kim HJ, Kim NC, Wang YD, et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013;495:467-473.

    Not in our library10.1038/nature11922

  123. 123.

    Kusui K. Epidemiological study on amyotrophic lateral sclerosis (ALS) and other neighboring motor neuron diseases in Kii Peninsula. Seishin Shinkeigaku Zasshi. 1962;64:85-99.

    Not in our library

  124. 124.

    Huang CC, Bose JK, Majumder P, et al. Metabolism and mis-metabolism of the neuropathological signature protein TDP-43. J Cell Sci. 2014;127:3024-3038.

    Not in our library10.1242/jcs.136150

  125. 125.

    Ishiura H, Takahashi Y, Mitsui J, et al. C9ORF72 repeat expansion in amyotrophic lateral sclerosis in the Kii peninsula of Japan. Arch Neurol. 2012;69:1154-1158.

    Not in our library10.1001/archneurol.2012.1219

  126. 126.

    Smith Bradley N, Ticozzi N, Fallini C, et al. Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron. 2014;84:324-331.

    Not in our library10.1016/j.neuron.2014.09.027

  127. 127.

    Smith BN, Vance C, Scotter EL, et al. Novel mutations support a role for Profilin1 in the pathogenesis of ALS. Neurobiol Aging 2014 Oct 31 [Epub ahead of print].

    Not in our library10.1016/j.neurobiolaging.2014.10.032

  128. 128.

    Sieh W, Choi Y, Chapman NH, et al. Identification of novel susceptibility loci for Guam neurodegenerative disease: challenges of genome scans in genetic isolates. Hum Mol Genet. 2009;18:3725-3738.

    Not in our library10.1093/hmg/ddp300

  129. 129.
    A role for human brain pericytes in neuroinflammation · 2014
    Corrected
  130. 130.

    Synofzik M, Born C, Rominger A, et al. Targeted high-throughput sequencing identifies a TARDBP mutation as a cause of early-onset FTD without motor neuron disease. Neurobiol Aging. 2014;35:1212 e1-5.

    Not in our library10.1016/j.neurobiolaging.2013.10.092

  131. 131.

    Johnson RT, Bradley W, Ritz B, Rocca WA, Shefner J, Wolfson C. Amyotrophic lateral sclerosis in veterans: Review of the scientific literature. United States of America: The National Academies Press, 2006, Report No.: 9780309102544.

    Not in our library

  132. 132.
    C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci · 2013
    No notice
  133. 133.

    Chio A, Calvo A, Dossena M, Ghiglione P, Mutani R, Mora G. ALS in Italian professional soccer players: the risk is still present and could be soccer-specific. Amyotroph Lateral Scler. 2009;10:205-209.

    Not in our library10.1080/17482960902721634

  134. 134.

    Orrell RW, Lane RJ, Ross M. A systematic review of antioxidant treatment for amyotrophic lateral sclerosis/motor neuron disease. Amyotroph Lateral Scler. 2008;9:195-211.

    Not in our library10.1080/17482960801900032

  135. 135.

    Polling S, Mok YF, Ramdzan YM, et al. Misfolded polyglutamine, polyalanine, and superoxide dismutase 1 aggregate via distinct pathways in the cell. J Biol Chem. 2014;289:6669-6680.

    Not in our library10.1074/jbc.m113.520189

  136. 136.

    Dewey CM, Cenik B, Sephton CF, et al. TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor. Mol Cell Biol 2010:MCB.01279-10.

    Not in our library10.1128/mcb.01279-10

  137. 137.
    Tar DNA Binding Protein-43 (TDP-43) Associates with Stress Granules: Analysis of Cultured Cells and Pathological Brain Tissue · 2010
    Corrected
  138. 138.

    McDonald KK, Aulas A, Destroismaisons L, et al. TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. Hum Mol Genet. 2011;20:1400-1410.

    Not in our library10.1093/hmg/ddr021

  139. 139.

    Udan-Johns M, Bengoechea R, Bell S, et al. Prion-like nuclear aggregation of TDP-43 during heat shock is regulated by HSP40/70 chaperones. Hum Mol Genet. 2014;23:157-170.

    Not in our library10.1093/hmg/ddt408

  140. 140.

    Dormann D, Haass C. TDP-43 and FUS: a nuclear affair. Trends Neurosci. 2011;34:339-348.

    Not in our library10.1016/j.tins.2011.05.002

  141. 141.

    Kim HJ, Raphael AR, LaDow ES, et al. Therapeutic modulation of eIF2alpha phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat Genet. 2014;46:152-160.

    Not in our library10.1038/ng.2853

  142. 142.

    Meyerowitz J, Parker SJ, Vella LJ, et al. C-Jun N-terminal kinase controls TDP-43 accumulation in stress granules induced by oxidative stress. Mol Neurodegener. 2011;6:57.

    Not in our library10.1186/1750-1326-6-57

  143. 143.

    Bentmann E, Neumann M, Tahirovic S, Rodde R, Dormann D, Haass C. Requirements for stress granule recruitment of fused in Sarcoma (FUS) and TAR DNA binding protein of 43 kDa (TDP-43). J Biol Chem. 2012;287:23079-23094.

    Not in our library10.1074/jbc.m111.328757

  144. 144.

    Dormann D, Rodde R, Edbauer D, et al. ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J. 2010;29:2841-2857.

    Not in our library10.1038/emboj.2010.143

  145. 145.
    Transgenic Rat Model of Neurodegeneration Caused by Mutation in the TDP Gene · 2010
    No notice
  146. 146.

    De Marco G, Lupino E, Calvo A, et al. Cytoplasmic accumulation of TDP-43 in circulating lymphomonocytes of ALS patients with and without TARDBP mutations. Acta Neuropathol. 2011;121:611-622.

    Not in our library10.1007/s00401-010-0786-7

  147. 147.
    Cytoplasmic Accumulation and Aggregation of TDP-43 upon Proteasome Inhibition in Cultured Neurons · 2011
    No notice
  148. 148.

    Igaz LM, Kwong LK, Lee EB, et al. Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J Clin Invest. 2011;121:726-738.

    Not in our library10.1172/jci44867

  149. 149.

    Igaz LM, Kwong LK, Xu Y, et al. Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Am J Pathol. 2008;173:182-194.

    Not in our library10.2353/ajpath.2008.080003

  150. 150.

    Suzuki H, Lee K, Matsuoka M. TDP-43-induced death is associated with altered regulation of BIM and Bcl-xL and attenuated by caspase-mediated TDP-43 cleavage. J Biol Chem. 2011;286:13171-13183.

    Not in our library10.1074/jbc.m110.197483

  151. 151.

    Dormann D, Capell A, Carlson AM, et al. Proteolytic processing of TAR DNA binding protein-43 by caspases produces C-terminal fragments with disease defining properties independent of progranulin. J Neurochem. 2009;110:1082-1094.

    Not in our library10.1111/j.1471-4159.2009.06211.x

  152. 152.

    Zhang YJ, Xu YF, Dickey CA, et al. Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43. J Neurosci. 2007;27:10530-10534.

    Not in our library10.1523/jneurosci.3421-07.2007

  153. 153.

    Fuentealba RA, Udan M, Bell S, et al. Interaction with polyglutamine aggregates reveals a Q/N-rich domain in TDP-43. J Biol Chem. 2010;285:26304-26314.

    Not in our library10.1074/jbc.m110.125039

  154. 154.

    Furukawa Y, Kaneko K, Nukina N. Molecular properties of TAR DNA binding protein-43 fragments are dependent upon its cleavage site. Biochim Biophys Acta. 1812;2011:1577-1583.

    Not in our library10.1016/j.bbadis.2011.09.005

  155. 155.
    The C-Terminal TDP-43 Fragments Have a High Aggregation Propensity and Harm Neurons by a Dominant-Negative Mechanism · 2010
    No notice
  156. 156.

    Che MX, Jiang YJ, Xie YY, Jiang LL, Hu HY. Aggregation of the 35-kDa fragment of TDP-43 causes formation of cytoplasmic inclusions and alteration of RNA processing. FASEB J. 2011;25:2344-2353.

    Not in our library10.1096/fj.10-174482

  157. 157.
    TDP-43-Mediated Neuron Loss In Vivo Requires RNA-Binding Activity · 2010
    No notice
  158. 158.

    Pesiridis GS, Tripathy K, Tanik S, Trojanowski JQ, Lee VM. A "two-hit" hypothesis for inclusion formation by carboxyl-terminal fragments of TDP-43 protein linked to RNA depletion and impaired microtubule-dependent transport. J Biol Chem. 2011;286:18845-18855.

    Not in our library10.1074/jbc.m111.231118

  159. 159.

    Van Langenhove T, van der Zee J, Van Broeckhoven C. The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Ann Med. 2012;44:817-828.

    Not in our library10.3109/07853890.2012.665471

  160. 160.
    Spliceosome integrity is defective in the motor neuron diseases ALS and SMA · 2013
    No notice
  161. 161.

    Jackrel ME, DeSantis ME, Martinez BA, et al. Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell. 2014;156:170-182.

    Not in our library10.1016/j.cell.2013.11.047

  162. 162.

    Gregory JM, Barros TP, Meehan S, Dobson CM, Luheshi LM. The aggregation and neurotoxicity of TDP-43 and its ALS-associated 25 kDa fragment are differentially affected by molecular chaperones in Drosophila. PLoS One. 2012;7:e31899.

    Not in our library10.1371/journal.pone.0031899

  163. 163.

    Crippa V, Carra S, Rusmini P, et al. A role of small heat shock protein B8 (HspB8) in the autophagic removal of misfolded proteins responsible for neurodegenerative diseases. Autophagy. 2010;6:958-960.

    Not in our library10.4161/auto.6.7.13042

  164. 164.

    Hasegawa M, Arai T, Nonaka T, et al. Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol. 2008;64:60-70.

    Not in our library10.1002/ana.21425

  165. 165.

    Inukai Y, Nonaka T, Arai T, et al. Abnormal phosphorylation of Ser409/410 of TDP-43 in FTLD-U and ALS. FEBS Lett. 2008;582:2899-2904.

    Not in our library10.1016/j.febslet.2008.07.027

  166. 166.

    Neumann M, Kwong LK, Lee EB, et al. Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol. 2009;117:137-149.

    Not in our library10.1007/s00401-008-0477-9

  167. 167.

    Kametani F, Nonaka T, Suzuki T, et al. Identification of casein kinase-1 phosphorylation sites on TDP-43. Biochem Biophys Res Commun. 2009;382:405-409.

    Not in our library10.1016/j.bbrc.2009.03.038

  168. 168.

    Iguchi Y, Katsuno M, Takagi S, et al. Oxidative stress induced by glutathione depletion reproduces pathological modifications of TDP-43 linked to TDP-43 proteinopathies. Neurobiol Dis. 2012;45:862-870.

    Not in our library10.1016/j.nbd.2011.12.002

  169. 169.
    Hyperphosphorylation as a defense mechanism to reduce TDP-43 aggregation. · 2011
    Not checked
  170. 170.

    Brady OA, Meng P, Zheng Y, Mao Y, Hu F. Regulation of TDP-43 aggregation by phosphorylation and p62/SQSTM1. J Neurochem. 2011;116:248-259.

    Not in our library10.1111/j.1471-4159.2010.07098.x

  171. 171.

    Choksi DK, Roy B, Chatterjee S, et al. TDP-43 Phosphorylation by casein kinase Iepsilon promotes oligomerization and enhances toxicity in vivo. Hum Mol Genet. 2014;23:1025-1035.

    Not in our library10.1093/hmg/ddt498

  172. 172.

    Salado IG, Redondo M, Bello ML, et al. Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis. J Med Chem. 2014;57:2755-2772.

    Not in our library10.1021/jm500065f

  173. 173.

    Seyfried NT, Gozal YM, Dammer EB, et al. Multiplex SILAC analysis of a cellular TDP-43 proteinopathy model reveals protein inclusions associated with SUMOylation and diverse polyubiquitin chains. Mol Cell Proteomics. 2010;9:705-718.

    Not in our library10.1074/mcp.m800390-mcp200

  174. 174.

    Hans F, Fiesel FC, Strong JC, et al. UBE2E ubiquitin-conjugating enzymes and ubiquitin isopeptidase Y regulate TDP-43 protein ubiquitination. J Biol Chem. 2014;289:19164-19179.

    Not in our library10.1074/jbc.m114.561704

  175. 175.

    Wenqiang C, Lonskaya I, Hebron ML, et al. Parkin-mediated reduction of nuclear and soluble TDP-43 reverses behavioral decline in symptomatic mice. Hum Mol Genet. 2014;23:4960-4969.

    Not in our library10.1093/hmg/ddu211

  176. 176.

    Gray DA, Tsirigotis M, Woulfe J. Ubiquitin, proteasomes, and the aging brain. Sci Aging Knowledge Environ. 2003;2003:RE6.

    Not in our library10.1126/sageke.2003.34.re6

  177. 177.
    Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study · 2012
    No notice

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