2. Academic Validation
  3. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement

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.
Sylvie Bannwarth 1,  Samira Ait-El-Mkadem 1,  Annabelle Chaussenot 1,  Emmanuelle C Genin 2,  Sandra Lacas-Gervais 3,  Konstantina Fragaki 1,  Laetitia Berg-Alonso 2,  Yusuke Kageyama 4,  Valérie Serre 5,  David G Moore 6,  Annie Verschueren 7,  Cécile Rouzier 1,  Isabelle Le Ber 8,  Gaëlle Augé 1,  Charlotte Cochaud 9,  Françoise Lespinasse 2,  Karine N'Guyen 10,  Anne de Septenville 11,  Alexis Brice 11,  Patrick Yu-Wai-Man 6,  Hiromi Sesaki 4,  Jean Pouget 7,  Véronique Paquis-Flucklinger 12
Affiliations

Affiliations

  • 1 1 IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France 2 Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France.
  • 2 1 IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France.
  • 3 3 Joint Centre for Applied Electron Microscopy, Nice Sophia-Antipolis University, France.
  • 4 4 Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 5 5 UMR7592 CNRS, Jacques Monod Institute, Paris Diderot University, France.
  • 6 6 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
  • 7 7 Department of Neurology, Timone Hospital, Marseille Teaching Hospital, France.
  • 8 8 Sorbonne Université, UPMC Univ Paris 06, UM75, Inserm U1127, Cnrs UMR7225, Institut du Cerveau et de la Moelle épinière (ICM), F-75013 Paris, France9 National Reference Centre on Rare Dementias, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
  • 9 2 Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France.
  • 10 10 Department of Medical Genetics, Timone Hospital, Marseille Teaching Hospital, France.
  • 11 8 Sorbonne Université, UPMC Univ Paris 06, UM75, Inserm U1127, Cnrs UMR7225, Institut du Cerveau et de la Moelle épinière (ICM), F-75013 Paris, France.
  • 12 1 IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France 2 Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France [email protected].
PMID: 24934289 DOI: 10.1093/brain/awu138
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.

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