The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity
Open Access
- 27 June 2016
- journal article
- video audio-media
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 22 (8), 869-878
- https://doi.org/10.1038/nm.4130
Abstract
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.Keywords
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