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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A CHCHD10 variant causing ALS elicits an unfolded protein response through the IRE1/XBP1 pathway
Isabella R Straub,Isabella R Straub,Woranontee Weraarpachai,Woranontee Weraarpachai,Eric A. Shoubridge,Eric A. Shoubridge +5 more
TL;DR: It is demonstrated that loss of CHCHD10 function elicits a striking energy deficit that activates cellular stress pathways, which may underlie the selective vulnerability of motor neurons.
Journal ArticleDOI
[A case of mitochondrial disease with multiple mitochondrial DNA deletions suspected amyotrophic lateral sclerosis-frontotemporal dementia].
TL;DR: The present case of a 76-year-old woman who showed a dramatic lowering of her tone of voice in October 2014, followed by muscle weakness of the left arm and a muscle biopsy revealed mitochondrial abnormality is considered to be valuable.
Posted ContentDOI
MFN2 Influences Amyotrophic Lateral Sclerosis Pathology
Kristi L. Russell,Jonathan M. Downie,Summer Gibson,Karla P. Figueroa,Cody J. Steely,Mark B. Bromberg,L. Charles Murtaugh,Lynn B. Jorde,Stefan M. Pulst +8 more
TL;DR: In this paper, the authors used sequence data from patients seen at the University of Utah to identify novel disease-associated loci and utilized both in vitro and in vivo studies to determine the biological effect of patient mutations in MFN2.
3D Reconstructions of Mouse Skeletal Muscle Reveal a Decrease in the MICOS Complex and Altered Mitochondrial Networks Serial Block-Face Scanning Electron Microscope (SBF-SEM) Processing of Mouse Muscle Liquid Chromatography-Mass Spectrometry
Zer Vue,Edgar Garza-Lopez,K. Neikirk,Lar L. Vang,H Beasley,Graziani Andrea,Marshall,Antentor J. Hinton +7 more
TL;DR: Similar changes in mitochondrial morphology were observed in aging skeletal muscles and for loss of MICOS proteins in mouse skeletal muscle, which suggests a differential response to mitochondrial aging in cardiac and skeletal muscle.
Journal ArticleDOI
Co-occurrence of amyotrophic lateral sclerosis and Leber’s hereditary optic neuropathy: is mitochondrial dysfunction a modifier?
Giulia Amore,Veria Vacchiano,Chiara La Morgia,Maria Lucia Valentino,Leonardo Caporali,Claudio Fiorini,Danara Ormanbekova,Fabrizio Salvi,Anna Bartoletti-Stella,Sabina Capellari,Rocco Liguori,Valerio Carelli +11 more
TL;DR: Indicating a peripheral accumulation of abnormal mitochondria and adenosine triphosphatase (ATPase) staining showed neurogenic changes with angulated, atrophic fibers and fiber type grouping.
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Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
Mariely DeJesus-Hernandez,Ian R. A. Mackenzie,Bradley F. Boeve,Adam L. Boxer,Matt Baker,Nicola J. Rutherford,Alexandra M. Nicholson,Ni Cole A. Finch,Heather C. Flynn,Jennifer Adamson,Naomi Kouri,Aleksandra Wojtas,Pheth Sengdy,Ging-Yuek Robin Hsiung,Anna Karydas,William W. Seeley,Keith A. Josephs,Giovanni Coppola,Daniel H. Geschwind,Zbigniew K. Wszolek,Howard Feldman,Howard Feldman,David S. Knopman,Ronald C. Petersen,Bruce L. Miller,Dennis W. Dickson,Kevin B. Boylan,Neill R. Graff-Radford,Rosa Rademakers +28 more
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
Alan E. Renton,Elisa Majounie,Adrian James Waite,Javier Simón-Sánchez,Javier Simón-Sánchez,Sara Rollinson,J. Raphael Gibbs,J. Raphael Gibbs,Jennifer C. Schymick,Hannu Laaksovirta,John C. van Swieten,John C. van Swieten,Liisa Myllykangas,Hannu Kalimo,Anders Paetau,Yevgeniya Abramzon,Anne M. Remes,Alice Kaganovich,Sonja W. Scholz,Sonja W. Scholz,Sonja W. Scholz,Jamie Duckworth,Jinhui Ding,Daniel W. Harmer,Dena G. Hernandez,Dena G. Hernandez,Janel O. Johnson,Janel O. Johnson,Kin Y. Mok,Mina Ryten,Danyah Trabzuni,Rita Guerreiro,Richard W. Orrell,James Neal,Alexandra Murray,J. P. Pearson,Iris E. Jansen,David Sondervan,Harro Seelaar,Derek J. Blake,Kate Young,Nicola Halliwell,Janis Bennion Callister,Greg Toulson,Anna Richardson,Alexander Gerhard,Julie S. Snowden,David M. A. Mann,David Neary,Mike A. Nalls,Terhi Peuralinna,Lilja Jansson,Veli-Matti Isoviita,Anna-Lotta Kaivorinne,Maarit Hölttä-Vuori,Elina Ikonen,Raimo Sulkava,Michael Benatar,Joanne Wuu,Adriano Chiò,Gabriella Restagno,Giuseppe Borghero,Mario Sabatelli,David Heckerman,Ekaterina Rogaeva,Lorne Zinman,Jeffrey D. Rothstein,Michael Sendtner,Carsten Drepper,Evan E. Eichler,Can Alkan,Ziedulla Abdullaev,Svetlana Pack,Amalia Dutra,Evgenia Pak,John Hardy,Andrew B. Singleton,Nigel Williams,Peter Heutink,Stuart Pickering-Brown,Huw R. Morris,Huw R. Morris,Huw R. Morris,Pentti J. Tienari,Bryan J. Traynor,Bryan J. Traynor +85 more
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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