The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity

• Published in: Nature medicine Vol. 22; no. 8; pp. 869 - 878
• Main Authors: Wang, Wenzhang, Wang, Luwen, Lu, Junjie, Siedlak, Sandra L, Fujioka, Hisashi, Liang, Jingjing, Jiang, Sirui, Ma, Xiaopin, Jiang, Zhen, da Rocha, Edroaldo Lummertz, Sheng, Max, Choi, Heewon, Lerou, Paul H, Li, Hu, Wang, Xinglong
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2016; Nature Publishing Group
• Subjects: 14/19; 14/28; 38/1; 38/23; 38/70; 38/91; 64/110; 692/699/375/132; 692/699/375/365/1917; 96/109; 96/44; Adult; Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Animals; Binding proteins; Bioenergetics; Biomedicine; Cancer Research; Cytoplasm; Degeneration; Dementia disorders; Deoxyribonucleic acid; DNA; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Electron Transport Complex I - genetics; Electron Transport Complex I - metabolism; Female; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Gene expression; Gene mutations; Genetics; Health aspects; Humans; Infectious Diseases; Innovations; Male; Metabolic Diseases; Mice; Mice, Transgenic; Middle Aged; Mitochondria; Mitochondria - metabolism; Molecular Medicine; Molecular targeted therapy; Mutants; Mutation; NADH Dehydrogenase - genetics; NADH Dehydrogenase - metabolism; Nervous system; Neurons - metabolism; Neurosciences; Phenotype; Properties; Proteins; RNA, Messenger; Toxicity
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4130

ALS-associated mutations in TDP-43 enhance its localization to mitochondria, and the inhibition of mitochondrial targeting reduces neuronal toxicity and alleviates motor phenotypes induced by TDP-43 expression in mice in vivo . Genetic mutations in TAR DNA-binding protein 43 ( TARDBP , also known as TDP-43 ) cause amyotrophic lateral sclerosis (ALS), and an increase in the presence of TDP-43 (encoded by TARDBP ) in the cytoplasm is a prominent histopathological feature of degenerating neurons in various neurodegenerative diseases. However, the molecular mechanisms by which TDP-43 contributes to ALS pathophysiology remain elusive. Here we have found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS or frontotemporal dementia (FTD). Disease-associated mutations increase TDP-43 mitochondrial localization. In mitochondria, wild-type (WT) and mutant TDP-43 preferentially bind mitochondria-transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunits ND3 and ND6, impair their expression and specifically cause complex I disassembly. The suppression of TDP-43 mitochondrial localization abolishes WT and mutant TDP-43-induced mitochondrial dysfunction and neuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice. Thus, our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose the targeting of TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration.