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

Jung-A. A. Woo, Tian Liu, Courtney Trotter, Cenxiao C. Fang, Emillio De Narvaez, Patrick LePochat, Drew Maslar, Anusha Bukhari, Xingyu Zhao, Andrew Deonarine, Sandy D. Westerheide and David E. Kang ()
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Jung-A. A. Woo: USF Health Byrd Alzheimer’s Institute, University of South Florida, Morsani College of Medicine
Tian Liu: USF Health Byrd Alzheimer’s Institute, University of South Florida, Morsani College of Medicine
Courtney Trotter: USF Health Byrd Alzheimer’s Institute, University of South Florida, Morsani College of Medicine
Cenxiao C. Fang: USF Health Byrd Alzheimer’s Institute, University of South Florida, Morsani College of Medicine
Emillio De Narvaez: USF Health Byrd Alzheimer’s Institute, University of South Florida, Morsani College of Medicine
Patrick LePochat: USF Health Byrd Alzheimer’s Institute, University of South Florida, Morsani College of Medicine
Drew Maslar: USF Health Byrd Alzheimer’s Institute, University of South Florida, Morsani College of Medicine
Anusha Bukhari: USF Health Byrd Alzheimer’s Institute, University of South Florida, Morsani College of Medicine
Xingyu Zhao: USF Health Byrd Alzheimer’s Institute, University of South Florida, Morsani College of Medicine
Andrew Deonarine: Microbiology & Molecular Biology, University of South Florida, College of Arts and Sciences
Sandy D. Westerheide: Microbiology & Molecular Biology, University of South Florida, College of Arts and Sciences
David E. Kang: USF Health Byrd Alzheimer’s Institute, University of South Florida, Morsani College of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15558

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