An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity

Guo, Weirui; Chen, Yanbo; Zhou, Xiao Hong; Kar, Amar N.; Ray, Payal; Chen, Xiaoping; Rao, Elizabeth J.; Yang, Mengxue; Ye, Haihong; Zhu, Li; Liu, Jianghong; Xu, Meng; Yang, Yanlian; Wang, Chen; Zhang, David; Bigio, Eileen H.; Mesulam, Marsel; Shen, Yan; Xu, Qi; Fushimi, Kazuo; Wu, Jane Y.

doi:10.1038/nsmb.2053

Cited by 281 publications

(287 citation statements)

References 49 publications

(58 reference statements)

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“…One possible source of toxicity may be from protein aggregation, as has been suggested for neurodegenerative diseases in general (19). TDP-43 is prone to aggregate, and ALS-linked mutants have a further elevated aggregation propensity (20)(21)(22). TDP-43 aggregation has been observed in some in vitro and in vivo models and is a hallmark in human ALS and FTLD (19).…”

mentioning

confidence: 99%

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

Yang

Wang

Qiao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

152

125

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Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease that causes motor neuron degeneration, progressive motor dysfunction, paralysis, and death. Although multiple causes have been identified for this disease, >95% of ALS cases show aggregation of transactive response DNA binding protein (TDP-43) accompanied by its nuclear depletion. Therefore, the TDP-43 pathology may be a converging point in the pathogenesis that originates from various initial triggers. The aggregation is thought to result from TDP-43 misfolding, which could generate cellular toxicity. However, the aggregation as well as the nuclear depletion could also lead to a partial loss of TDP-43 function or TDP-43 dysfunction. To investigate the impact of TDP-43 dysfunction, we generated a transgenic mouse model for a partial loss of TDP-43 function using transgenic RNAi. These mice show ubiquitous transgene expression and TDP-43 knockdown in both the periphery and the central nervous system (CNS). Strikingly, these mice develop progressive neurodegeneration prominently in cortical layer V and spinal ventral horn, motor dysfunction, paralysis, and death. Furthermore, examination of splicing patterns of TDP-43 target genes in human ALS revealed changes consistent with TDP-43 dysfunction. These results suggest that the CNS, particularly motor neurons, possess a heightened vulnerability to TDP-43 dysfunction. Additionally, because TDP-43 knockdown predominantly occur in astrocytes in the spinal cord of these mice, our results suggest that TDP-43 dysfunction in astrocytes is an important driver for motor neuron degeneration and clinical phenotypes of ALS.

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mentioning

confidence: 99%

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

Yang

Wang

Qiao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

152

125

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“…Moreover, the newly aggregated TDP43 maintained characteristic biochemical properties reminiscent of prion Bstrains^originally described in mammalian prion diseases [124,125]. fALS-associated mutations in TARDBP are clustered within the prion-like domain of TDP43 [27], and enhance the self-aggregation and seeding behavior of TDP43 fragments [126,127]. Likewise, mutations in the prion-like domain of hnRNP A1 and hnRNP A2/B1 that cause multisystem proteinopathy facilitate self-aggregation of peptides bearing the mutations, and accelerate the aggregation of WT hnRNP isoforms through a seeding mechanism [10].…”

Section: Alternative Rna-based Mechanismsmentioning

confidence: 88%

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Barmada

2015

Neurotherapeutics

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The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS.

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“…In particular, TDP-43-A315T mice develop later onset paralysis with cytoplasmic ubiquitin inclusions, gliosis and TDP-43 redistribution and fragmentation (Stallings et al, 2010). Moreover, in vivo and also in vitro the A315T mutant enhances neurotoxicity and the formation of aberrant TDP-43 species, including protease-resistant fragments (Guo et al, 2011). Moderate overexpression of hTDP-43 results in TDP-43 truncation, increased cytoplasmic and nuclear ubiquitin levels, intranuclear and cytoplasmic aggregates immunopositive for phosphorylated TDP-43.…”

Section: Tdp-43 Mutationsmentioning

confidence: 99%