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Hum Mol Genet. 2013 Dec 1;22(23):4706-19. doi: 10.1093/hmg/ddt319. Epub 2013 Jul 4.

The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons.

Author information

1
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.

Abstract

Mutations in TDP-43 lead to familial ALS. Expanding evidence suggests that impaired mitochondrial dynamics likely contribute to the selective degeneration of motor neurons in SOD1-associated ALS. In this study, we investigated whether and how TDP-43 mutations might impact mitochondrial dynamics and function. We demonstrated that overexpression of wild-type TDP-43 resulted in reduced mitochondrial length and density in neurites of primary motor neurons, features further exacerbated by ALS-associated TDP-43 mutants Q331K and M337V. In contrast, suppression of TDP-43 resulted in significantly increased mitochondrial length and density in neurites, suggesting a specific role of TDP-43 in regulating mitochondrial dynamics. Surprisingly, both TDP-43 overexpression and suppression impaired mitochondrial movement. We further showed that abnormal localization of TDP-43 in cytoplasm induced substantial and widespread abnormal mitochondrial dynamics. TDP-43 co-localized with mitochondria in motor neurons and their colocalization was enhanced by ALS associated mutant. Importantly, co-expression of mitochondrial fusion protein mitofusin 2 (Mfn2) could abolish TDP-43 induced mitochondrial dynamics abnormalities and mitochondrial dysfunction. Taken together, these data suggest that mutant TDP-43 impairs mitochondrial dynamics through enhanced localization on mitochondria, which causes mitochondrial dysfunction. Therefore, abnormal mitochondrial dynamics is likely a common feature of ALS which could be potential new therapeutic targets to treat ALS.

PMID:
23827948
PMCID:
PMC3820133
DOI:
10.1093/hmg/ddt319
[Indexed for MEDLINE]
Free PMC Article

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