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The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons
Open accessAbstract
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.
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Cites
Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
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Functions and dysfunctions of mitochondrial dynamics
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Self-citationLocal translation of extranuclear lamin B promotes axon maintenance
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Cited by
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Yu, C.-H., Davidson, S., Harapas, C. R., Hilton, J. B., Mlodzianoski, M. J., Laohamonthonkul, P., Louis, C., Low, R. R. J., Moecking, J., De Nardo, D., et al. (2020) · Cell · doi:10.1016/j.cell.2020.09.020 · Cited by 1,019
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis
Prasad, A., Bharathi, V., Sivalingam, V., Girdhar, A., & Patel, B. K. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00025 · Cited by 774
Axonal Transport of TDP-43 mRNA Granules Is Impaired by ALS-Causing Mutations
Alami, N. H., Smith, R. B., Carrasco, M. A., Williams, L. A., Winborn, C. S., Han, S. S. W., Kiskinis, E., Winborn, B., Freibaum, B. D., Kanagaraj, A., et al. (2014) · Neuron · doi:10.1016/j.neuron.2013.12.018 · Cited by 660
Nuclear speckles: molecular organization, biological function and role in disease
Galganski, L., Urbanek, M. O., & Krzyzosiak, W. J. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx759 · Cited by 499
Oxidative Stress in Neurodegenerative Diseases: From a Mitochondrial Point of View
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Metadata
- Authors
- Wang, W., Li, L., Lin, W.-L., Dickson, D. W., Petrucelli, L., Zhang, T., & Wang, X.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-07-04
- Volume
- 22
- Issue
- 23
- Pages
- 4706-4719
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2112710669
- Cited by
- 338
- References
- 8
- FWCI
- 10.07
- Type
- journal article
- Language
- en
- Open access
- bronze
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