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

Wenzhang Wang, Luwen Wang, Junjie Lu, Sandra L. Siedlak, Hisashi Fujioka, Jingjing Liang, Sirui Jiang, Xiaopin Ma, Zhen Jiang, Edroaldo Lummertz Da Rocha, Max Sheng, Heewon Choi, Paul H. Lerou, Hu Li, Xinglong Wang

Research output: Contribution to journalArticlepeer-review

142 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)869-878
Number of pages10
JournalNature Medicine
Volume22
Issue number8
DOIs
StatePublished - Aug 1 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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