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.
| Original language | English (US) |
|---|---|
| Journal | The EMBO Journal |
| Volume | 37 |
| Issue number | 23 |
| DOIs | |
| State | Published - Nov 12 2018 |
Bibliographical note
KAUST Repository Item: Exported on 2020-10-01Acknowledged KAUST grant number(s): FCC/1/1976-21
Acknowledgements: 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.
