Journal Article

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

Woo, Jung-A. A., Maslar, Drew, Bukhari, Anusha, Westerheide, Sandy D., De Narvaez, Emillio, Liu, Tian, LePochat, Patrick, Zhao, Xingyu, Deonarine, Andrew, Kang, David E., Trotter, Courtney, Fang, Cenxiao C.

2017

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 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 / Dementia disorders / DNA-Binding Proteins - metabolism / Frontotemporal Dementia - genetics / Genetic Complementation Test / HEK293 Cells / Humanities and Social Sciences / Humans / Mammals / 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