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.

The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction

“…Little is known, however, about the physiological role of CHCHD10 (7). Most studies have focused on characterizing CHCHD10's effects in mitochondria by testing the effects of pathogenic mutations in a cell culture system (8,9,14). These studies have suggested that CHCHD10 affects stability of mitochondrial cristae (9, 14), COX activity (7), formation of mitochondrial networks (8), stability of mitochondrial DNA, and apoptosis (14).…”

“…domaincontaining 10 (CHCHD10) and CHCHD2 (MNRR1) are homologous proteins with 58% sequence identity and belong to the twin CX 9 C family of proteins that mediate cellular stress responses. Despite the identification of several neurodegeneration-associated mutations in the CHCHD10 gene, few studies have assessed its physiological role.…”

Mitochondrial Proteins Containing Coiled-Coil-Helix-Coiled-Coil-Helix (CHCH) Domains in Health and Disease

“…In human cells, the activity of the soluble IMS-localized (CX 9 C) 2 motif-carrying protein 238 CHCHD10 ( Table 1), which is enriched in cristae junctions, impacts mitochondrial 239 ultrastructure through hitherto poorly understood mechanisms [98]. A missense mutation 240 (S59L) in CHCHD10 that is associated with frontotemporal dementia (FTD) and amyotrophic 241 lateral sclerosis (ALS) [98,99] causes respiratory deficiencies accompanied by mitochondrial 242 dysgenesis and fragmentation in patient fibroblasts [98] (Table 2).…”

“…A missense mutation 240 (S59L) in CHCHD10 that is associated with frontotemporal dementia (FTD) and amyotrophic 241 lateral sclerosis (ALS) [98,99] causes respiratory deficiencies accompanied by mitochondrial 242 dysgenesis and fragmentation in patient fibroblasts [98] (Table 2). CHCHD10 and its 243 paralogue CHCHD2, which are encoded by genes localized on chromosomes 22q11.23 and 244 7p11.2, respectively, have emerged as a result of gene duplication during the evolution from 245 yeast to man [49].…”

The genetic basis of amyotrophic lateral sclerosis: recent breakthroughs

“…198,199 Exome sequencing in parent-case offspring trios has already been employed for the investigation of de novo mutations in SALS. [200][201][202] To this end, de novo mutations have been found in genes encoding chromatin regulators, including the neuronal chromatin remodeling complex (nBAF) component SS18L1 (also known as CREST).…”