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

Topic: Brain proteins, microglia and lab models

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.

Key findings

• The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder.
• Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts.

Why it matters

In one large family, a mutation in the CHCHD10 gene was linked to a late-onset condition including motor neuron disease and cognitive decline resembling frontotemporal dementia, with signs of mitochondrial problems. This is genetic research into a rare disorder and does not test any treatment, cure or prevention for Alzheimer's disease.

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Study details

• Evidence strengthModerate

Read the original

• DOI: 10.1093/brain/awu138
• PubMed: 24934289
• Original source →
• Free full text: PubMed Central →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{bannwarth2014-24934289,
  author  = {Bannwarth, S. and Ait-El-Mkadem, S. and Chaussenot, A. and Genin, E. C. and Lacas-Gervais, S. and Fragaki, K. and Berg-Alonso, L. and Kageyama, Y. and others},
  title   = {{A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement}},
  journal = {Brain : a journal of neurology},
  year    = {2014},
  doi     = {10.1093/brain/awu138},
  pmid    = {24934289},
  url     = {https://doi.org/10.1093/brain/awu138}
}

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