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Nat Commun. 2017 Jun 6;8:15558. doi: 10.1038/ncomms15558.

Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity.

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USF Health Byrd Alzheimer's Institute, University of South Florida, Morsani College of Medicine, Tampa, Florida 33613, USA.
Department of Molecular Medicine, University of South Florida, Morsani College of Medicine, Tampa, Florida 33613, USA.
Department of Cell Biology, Microbiology &Molecular Biology, University of South Florida, College of Arts and Sciences, Tampa, Florida 33620, USA.
James A. Haley Veteran's Administration Hospital, Tampa, Florida 33612, USA.


Although multiple CHCHD10 mutations are associated with the spectrum of familial and sporadic frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) diseases, neither the normal function of endogenous CHCHD10 nor its role in the pathological milieu (that is, TDP-43 pathology) of FTD/ALS have been investigated. In this study, we made a series of observations utilizing Caenorhabditis elegans models, mammalian cell lines, primary neurons and mouse brains, demonstrating that CHCHD10 normally exerts a protective role in mitochondrial and synaptic integrity as well as in the retention of nuclear TDP-43, whereas FTD/ALS-associated mutations (R15L and S59L) exhibit loss of function phenotypes in C. elegans genetic complementation assays and dominant negative activities in mammalian systems, resulting in mitochondrial/synaptic damage and cytoplasmic TDP-43 accumulation. As such, our results provide a pathological link between CHCHD10-associated mitochondrial/synaptic dysfunction and cytoplasmic TDP-43 inclusions.

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