A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement
Sylvie Bannwarth,Samira Ait-El-Mkadem,Annabelle Chaussenot,Emmanuelle C. Genin,Sandra Lacas-Gervais,Konstantina Fragaki,Laetitia Berg-Alonso,Yusuke Kageyama,Valérie Serre,David Moore,Annie Verschueren,Cécile Rouzier,Isabelle Le Ber,Gaëlle Augé,Charlotte Cochaud,Françoise Lespinasse,Karine Nguyen,Anne de Septenville,Alexis Brice,Patrick Yu-Wai-Man,Hiromi Sesaki,Jean Pouget,Véronique Paquis-Flucklinger +22 more
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A large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy is reported, showing that mitochondrial disease may be at the origin of some of these phenotypes.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.read more
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Dissertation
The genetic landscape of amyotrophic lateral sclerosis
TL;DR: Many cases of ALS, sporadic included, show a complex genetic interplay which, combined with the overall mutation burden, determine the risk and course of ALS.
Book ChapterDOI
Genetics and Epigenetics in the Neurodegenerative Disorders of the Central Nervous System
TL;DR: Most of the neurodegenerative diseases share several clinical, pathologic, and molecular aspects, but dementia is not only peculiar of Alzheimer’s disease (AD) or frontotemporal dementia (FTD), but could occur also in Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS).
Journal ArticleDOI
Boosting Mitochondrial Potential: An Imperative Therapeutic Intervention in Amyotrophic Lateral Sclerosis
TL;DR: A review of the latest developments in the understanding of mitochondrial pathogenesis in ALS and emphasize the restorative capacity of therapeutic candidates is presented in this article , where some of the therapies classified as synthetic, natural compounds, genetic materials, and cellular therapies.
Dissertation
Gene expression profiling and functional studies of astrocytes in SOD1-related amyotrophic lateral sclerosis
TL;DR: The breadth of behaviours displayed by astrocytes during ALS disease progression is shown and will provide an important guide for future therapeutic intervention.
Posted ContentDOI
Regional collapsing of rare variation implicates specific genic regions in ALS
Sahar Gelfman,Sarah A. Dugger,Cristiane de Araújo Martins Moreno,Zhong Ren,Charles J. Wolock,Neil A. Shneider,Hemali Phatnani,Elizabeth T. Cirulli,Brittany N. Lasseigne,Timothy D. Harris,Tom Maniatis,Guy A. Rouleau,Robert H. Brown,Aaron D. Gitler,Richard M. Myers,Slavé Petrovski,Andrew S. Allen,Matthew B. Harms,David Goldstein +18 more
TL;DR: Two collapsing strategies are developed, one focuses rare variation collapsing on homology-based protein domains as the unit for collapsing and another gene-level approach that leverages existing evidence of purifying selection against missense variation on said domains.
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Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
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TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.
Journal ArticleDOI
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
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TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
Journal ArticleDOI
Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.
Stephan Züchner,Stephan Züchner,Irina V. Mersiyanova,Maria Muglia,Nisrine Bissar-Tadmouri,Nisrine Bissar-Tadmouri,Julie M. Rochelle,Elena L. Dadali,Mario Zappia,Eva Nelis,Alessandra Patitucci,Jan Senderek,Yesim Parman,Oleg V. Evgrafov,Peter De Jonghe,Yuji Takahashi,Shoij Tsuji,Margaret A. Pericak-Vance,Aldo Quattrone,Esra Battologlu,Alexander V. Polyakov,Vincent Timmerman,J. Michael Schröder,Jeffery M. Vance +23 more
TL;DR: It is concluded that the primary gene mutated in CMT2A is MFN2, and seven large pedigrees affected with Charcot-Marie-Tooth neuropathy type 2A are concluded.
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