Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

TitleLoss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
Publication TypeJournal Article
Year of Publication2018
AuthorsShashi, V, Magiera, MM, Klein, D, Zaki, M, Schoch, K, Rudnik-Schöneborn, S, Norman, A, Neto, OLopes Abat, Dusl, M, Yuan, X, Bartesaghi, L, De Marco, P, Alfares, AA, Marom, R, Arold, ST, Guzmán-Vega, FJ, Pena, LDm, Smith, EC, Steinlin, M, Babiker, MOe, Mohassel, P, A Foley, R, Donkervoort, S, Kaur, R, Ghosh, PS, Stanley, V, Musaev, D, Nava, C, Mignot, C, Keren, B, Scala, M, Tassano, E, Picco, P, Doneda, P, Fiorillo, C, Issa, MY, Alassiri, A, Alahmad, A, Gerard, A, Liu, P, Yang, Y, Ertl-Wagner, B, Kranz, PG, Wentzensen, IM, Stucka, R, Stong, N, Allen, AS, Goldstein, DB, Schoser, B, Rösler, KM, Alfadhel, M, Capra, V, Chrast, R, Strom, TM, Kamsteeg, E-J, Bönnemann, CG, Gleeson, JG, Martini, R, Janke, C, Senderek, J
Corporate AuthorsUndiagnosed Diseases Network
JournalEMBO J
Date Published2018 Dec 03

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 () 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 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.

Alternate JournalEMBO J.
PubMed ID30420557
PubMed Central IDPMC6276871
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
U01 HG007672 / HG / NHGRI NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
R01 NS098004 / NS / NINDS NIH HHS / United States