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

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

Author information

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 paquis@hermes.unice.fr.

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

Comment in

PMID:
24934289
PMCID:
PMC4107737
DOI:
10.1093/brain/awu138
[Indexed for MEDLINE]
Free PMC Article

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