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

Nat Commun. 2017 Jun 6;8:15558. doi: 10.1038/ncomms15558.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Caenorhabditis elegans / genetics*
  • Cell Line
  • Cytoplasm / metabolism
  • DNA-Binding Proteins / metabolism*
  • Frontotemporal Dementia / genetics*
  • Genetic Complementation Test
  • HEK293 Cells
  • Humans
  • Mice
  • Microscopy, Fluorescence
  • Mitochondria / metabolism
  • Mitochondrial Proteins / genetics*
  • Mutation
  • NIH 3T3 Cells
  • Neurons / metabolism
  • Phenotype
  • Protein Binding
  • Protein Domains
  • RNA, Small Interfering / metabolism
  • Synapses / metabolism*
  • Transgenes


  • CHCHD10 protein, human
  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • RNA, Small Interfering
  • TARDBP protein, human
  • TDP-43 protein, mouse

Supplementary concepts

  • Frontotemporal Dementia With Motor Neuron Disease