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

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

doi:10.1038/ncomms15558

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.

Highlights

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 of Frontotemporal dementia (FTD)/ALS have been investigated
All quantitative graphs with error bars were expressed as mean±s.e.m
The R15 and S59 CHCHD10 residues mutated in FTD/ALS are conserved between C. elegans har-1 and human CHCHD10 proteins (Fig. 1a)

Summary

Introduction

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. Compared to control and WT CHCHD10, neurons transduced with R15L or S59L CHCHD10 mutants demonstrated significant increases in the ratios of endogenous cytoplasmic/nuclear TDP-43 staining (Fig. 6c,d).

Results

Conclusion