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

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.

• Authors: Sylvie Bannwarth, Samira Ait-El-Mkadem, Annabelle Chaussenot, Emmanuelle C Genin, Sandra Lacas-Gervais, Konstantina Fragaki, Laetitia Berg-Alonso, Yusuke Kageyama, Valérie Serre, David G Moore, Annie Verschueren, Cécile Rouzier, Isabelle Le Ber, Gaëlle Augé, Charlotte Cochaud, Françoise Lespinasse, Karine N'Guyen, Anne de Septenville, Alexis Brice, Patrick Yu-Wai-Man, Hiromi Sesaki, Jean Pouget, Véronique Paquis-Flucklinger
• Journal: Brain : a journal of neurology (Brain) Vol. 137 Issue Pt 8 Pg. 2329-45 (Aug 2014) ISSN: 1460-2156 [Electronic] England
• PMID: 24934289 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected].

Chemical References

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

Topics

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