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

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 hav...

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Published in:	Nature communications Vol. 8; no. 1; p. 15558
Main Authors:	Woo, Jung-A. A., Liu, Tian, Trotter, Courtney, Fang, Cenxiao C., De Narvaez, Emillio, LePochat, Patrick, Maslar, Drew, Bukhari, Anusha, Zhao, Xingyu, Deonarine, Andrew, Westerheide, Sandy D., Kang, David E.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 06-06-2017 Nature Publishing Group Nature Portfolio
Subjects:	13/109 14/19 38/89 42/70 631/378/1689/1285 631/378/1689/364 631/378/1934 631/80/304 64/11 64/60 96/2 96/95 Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis - genetics Animals Caenorhabditis elegans - genetics Cell Line Cytoplasm - metabolism DNA-Binding Proteins - metabolism Frontotemporal Dementia - genetics Genetic Complementation Test HEK293 Cells Humanities and Social Sciences Humans Mice Microscopy, Fluorescence Mitochondria - metabolism Mitochondrial Proteins - genetics Motility multidisciplinary Mutation Neurons - metabolism NIH 3T3 Cells Pathology Phenotype Protein Binding Protein Domains Proteins RNA, Small Interfering - metabolism Science Science (multidisciplinary) Synapses - metabolism Transgenes Worms Florida United States > US
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Summary:	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. Mutations in CHCHD10 have been recently associated with frontotemporal dementia and amyotrophic lateral sclerosis. Here the authors study the functions of endogenous CHCHD10 in Caenorhabditis elegans , primary neurons, and mouse, and show that it normally protects mitochondria and synaptic integrity, and retains TDP-43 in the nucleus.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms15558