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

Topic: Brain proteins, microglia and lab models

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.

@article{woo2017-28585542,
  author  = {Woo, J. A. and Liu, T. and Trotter, C. and Fang, C. C. and De Narvaez, E. and LePochat, P. and Maslar, D. and Bukhari, A. and others},
  title   = {{Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity}},
  journal = {Nature communications},
  year    = {2017},
  doi     = {10.1038/ncomms15558},
  pmid    = {28585542},
  url     = {https://doi.org/10.1038/ncomms15558}
}

Key findings

• 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.
• As such, our results provide a pathological link between CHCHD10-associated mitochondrial/synaptic dysfunction and cytoplasmic TDP-43 inclusions.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/ncomms15558
• PubMed: 28585542
• Original source →

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