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    Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration

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    Type
    Article
    Authors
    Shashi, Vandana
    Magiera, Maria M
    Klein, Dennis
    Zaki, Maha
    Schoch, Kelly
    Rudnik-Schöneborn, Sabine
    Norman, Andrew
    Lopes Abath Neto, Osorio
    Dusl, Marina
    Yuan, Xidi
    Bartesaghi, Luca
    De Marco, Patrizia
    Alfares, Ahmed A
    Marom, Ronit
    Arold, Stefan T. cc
    Guzmán-Vega, Francisco J. cc
    Pena, Loren DM
    Smith, Edward C
    Steinlin, Maja
    Babiker, Mohamed OE
    Mohassel, Payam
    Foley, A. Reghan
    Donkervoort, Sandra
    Kaur, Rupleen
    Ghosh, Partha S
    Stanley, Valentina
    Musaev, Damir
    Nava, Caroline
    Mignot, Cyril
    Keren, Boris
    Scala, Marcello
    Tassano, Elisa
    Picco, Paolo
    Doneda, Paola
    Fiorillo, Chiara
    Issa, Mahmoud Y
    Alassiri, Ali
    Alahmad, Ahmed
    Gerard, Amanda
    Liu, Pengfei
    Yang, Yaping
    Ertl-Wagner, Birgit
    Kranz, Peter G
    Wentzensen, Ingrid M
    Stucka, Rolf
    Stong, Nicholas
    Allen, Andrew S
    Goldstein, David B
    Schoser, Benedikt
    Rösler, Kai M
    Alfadhel, Majid
    Capra, Valeria
    Chrast, Roman
    Strom, Tim M
    Kamsteeg, Erik-Jan
    Bönnemann, Carsten G
    Gleeson, Joseph G
    Martini, Rudolf
    Janke, Carsten
    Senderek, Jan
    Undiagnosed Diseases Network
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    Computational Bioscience Research Center (CBRC)
    Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
    KAUST Grant Number
    FCC/1/1976-21
    Date
    2018-11-12
    Online Publication Date
    2018-11-12
    Print Publication Date
    2018-12-03
    Permanent link to this record
    http://hdl.handle.net/10754/630602
    
    Metadata
    Show full item record
    Abstract
    A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the Purkinje cell degeneration (pcd) mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.
    Citation
    Shashi V, Magiera MM, Klein D, Zaki M, Schoch K, et al. (2018) Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration. The EMBO Journal 37: e100540. Available: http://dx.doi.org/10.15252/embj.2018100540.
    Sponsors
    We thank the families for participating in this study. We are grateful to Jijumon A. S. (Institut Curie) for technical help and S. Lacomme, M. Landry, and A. Calas (Université Bordeaux) for data on pcd pathology. CGB thanks C. Mendoza and G. Averion for their help in the clinic. MMM received a fellowship from the European Molecular Biology Organization (ASTF 148-2015), MD from the Bayerische Gleichstellungsförderung, and R. Marom from the Osteogenesis Imperfecta Foundation. This work was supported by the National Institutes of Health (NIH) Common Fund (1U01HG007672-01; to VSh and DBG), the Fondation Vaincre Alzheimer (FR-16055p; to MMM), the German Federal Ministry of Education and Research (BMBF) through the German Network for Charcot-Marie-Tooth neuropathies (CMT-NET) (01GM1511B, 01GM1511D, 01GM1511F; to DK, SR-S, RMart and JS), the King Abdullah University of Science and Technology (baseline fund and Award No FCC/1/1976-21; to STA and FJGV), the Swedish StratNeuro program (to RC), the National Institute of Neurological Disorders and Stroke (to CGB), the NIH (R01NS098004, R01NS048453; to JGG), the French National Research Agency (ANR) (ANR-12-BSV2-0007; to CJ), the program “Investissements d'Avenir” of the French government and ANR (ANR-10-LBX-0038, ANR-10-IDEX-0001-02 PSL; to CJ), the Institut Curie (to CJ), the Institut National du Cancer (2013-1-PL BIO-02-ICR-1, 2014-PL BIO-11-ICR-1; to CJ), the Fritz-Thyssen-Stiftung (Az.10.15.1.021MN; to JS), and the Friedrich-Baur-Stiftung (to JS). WES was funded through the Clinical Center Genomics Opportunity, sponsored by the National Human Genome Research Institute, the NIH Deputy Director for Intramural Research and the NIH Clinical Center, the Broad Joint Center for Mendelian Genomics (UM1 HG008900; to D. MacArthur and H. Rehm), and the Yale Center for Mendelian Disorders (U54HG006504; to R. Lifton, M. Günel, M. Gerstein and S. Mane). This study makes use of data shared through the Broad Institute matchbox repository. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
    Publisher
    EMBO
    Journal
    The EMBO Journal
    DOI
    10.15252/embj.2018100540
    Additional Links
    http://emboj.embopress.org/content/early/2018/11/12/embj.2018100540
    ae974a485f413a2113503eed53cd6c53
    10.15252/embj.2018100540
    Scopus Count
    Collections
    Articles; Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program; Computational Bioscience Research Center (CBRC); Computer, Electrical and Mathematical Science and Engineering (CEMSE) Division

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