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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.

Author information

1
USF Health Byrd Alzheimer's Institute, University of South Florida, Morsani College of Medicine, Tampa, Florida 33613, USA.
2
Department of Molecular Medicine, University of South Florida, Morsani College of Medicine, Tampa, Florida 33613, USA.
3
Department of Cell Biology, Microbiology &Molecular Biology, University of South Florida, College of Arts and Sciences, Tampa, Florida 33620, USA.
4
James A. Haley Veteran's Administration Hospital, Tampa, Florida 33612, USA.

Abstract

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.

PMID:
28585542
PMCID:
PMC5467170
DOI:
10.1038/ncomms15558
[Indexed for MEDLINE]
Free PMC Article

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