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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TLDR
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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The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations
TL;DR: How UPRER and UPRmt signaling changes in the context of aging and neurodegeneration are discussed, and therapeutic strategies targeting the UPR ER andUPRmt are highlighted that may improve human health are highlighted.
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Neuroimaging in genetic frontotemporal dementia and amyotrophic lateral sclerosis
TL;DR: This review focuses on the current understanding of structural, functional and molecular neuroimaging signatures of genetic FTD and ALS.
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CHCHD10 variants in amyotrophic lateral sclerosis: where is the evidence?
Gijs H.P. Tazelaar,Wouter van Rheenen,Sara L. Pulit,Rick A.A. van der Spek,Annelot M. Dekker,Matthieu Moisse,Russell L. McLaughlin,William Sproviero,Kevin P. Kenna,Maarten Kooyman,Perry T.C. van Doormaal,Kristel E. van Eijk,Bas Middelkoop,Raymond D. Schellevis,William J. Brands,Ammar Al-Chalabi,Karen E. Morrison,Pamela J. Shaw,Christopher Shaw,Stephen E. Newhouse,Michael A. van Es,A. Nazli Basak,Fulya Akçimen,Cemile Kocoglu,Ceren Tunca,Mònica Povedano,Jesus S. Mora,Jonathan D. Glass,Philip Van Damme,Wim Robberecht,Orla HardimanMD,John Landers,Leonard H. van den Berg,Jan H. Veldink +33 more
TL;DR: The role of CHCHD10 mutations in ALS is determined and the exact pathogenicity and clinical significance of these mutations remain unclear.
Journal ArticleDOI
Intrafamilial clinical variability in individuals carrying the CHCHD10 mutation Gly66Val.
Petra Pasanen,Liisa Myllykangas,Minna Pöyhönen,Sari Kiuru-Enari,Pentti J. Tienari,Pentti J. Tienari,Hannu Laaksovirta,Hannu Laaksovirta,Jussi Toppila,Emil Ylikallio,Henna Tyynismaa,Mari Auranen,Mari Auranen +12 more
TL;DR: Assessment of clinical variability in a large family carrying the p.Gly66Val mutation of the CHCHD10 gene, which has recently been reported to cause late‐onset spinal muscular atrophy (SMAJ) or sensorimotor axonal Charcot–Marie–Tooth neuropathy (CMT2) in the Finnish population.
Journal ArticleDOI
Reply: High prevalence of CHCHD10 mutations in patients with frontotemporal dementia from China.
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,Patrick Yu-Wai-Man,Hiromi Sesaki,Jean Pouget,Véronique Paquis-Flucklinger +23 more
TL;DR: Data is presented showing that the CHCHD10 mutation is common in patients with the pure FTD phenotype in China, the first report proposing that mitochondrial dysfunction contributes to the pathogenesis of ALS and FTD.
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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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