title: The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons.
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.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Wenzhang
authors.initials: W
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Lin
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.forename: Teng
authors.initials: T
authors.lastname: Zhang
authors.forename: Xinglong
authors.initials: X
authors.lastname: Wang
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D020558:GTP Phosphohydrolases; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000502:physiology; D009046:Motor Neurons / Q000473:pathology / Q000502:physiology*; D009154:Mutation; D016501:Neurites / Q000378:metabolism / Q000648:ultrastructure; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic
chemical_list: D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat