A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement

Brain. 2014 Aug;137(Pt 8):2329-45. doi: 10.1093/brain/awu138. Epub 2014 Jun 16.

Abstract

Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes.

Keywords: CHCHD10; FTD-ALS; mitochondrial DNA instability; mitochondrial disorder.

Publication types

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

MeSH terms

  • Age of Onset
  • Aged
  • Alleles
  • Amyotrophic Lateral Sclerosis / etiology*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / physiopathology
  • DNA, Mitochondrial / genetics*
  • Exome / genetics
  • Female
  • Frontotemporal Dementia / etiology*
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / physiopathology
  • HeLa Cells
  • Humans
  • Male
  • Middle Aged
  • Mitochondria / genetics
  • Mitochondria / pathology*
  • Mitochondrial Diseases / complications*
  • Mitochondrial Diseases / genetics
  • Mitochondrial Proteins / genetics*
  • Mutation, Missense
  • Pedigree
  • Phenotype

Substances

  • CHCHD10 protein, human
  • DNA, Mitochondrial
  • Mitochondrial Proteins