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Shashi, V.* ; Magiera, M.M.* ; Klein, D.* ; Zaki, M.* ; Schoch, K.* ; Rudnik-Schöneborn, S.* ; Norman, A.* ; Lopes Abath Neto, O.* ; Dusl, M.* ; Yuan, X.* ; Bartesaghi, L.* ; De Marco, P.* ; Alfares, A.A.* ; Marom, R.* ; Arold, S.T.* ; Guzmán-Vega, F.J.* ; Pena, L.D.M.* ; Smith, E.C.* ; Steinlin, M.* ; Babiker, M.O.E.* ; Mohassel, P.* ; Foley, A.R.* ; Donkervoort, S.* ; Kaur, R.* ; Ghosh, P.S.* ; Stanley, V.* ; Musaev, D.* ; Nava, C.* ; Mignot, C.* ; Keren, B.* ; Scala, M.* ; Tassano, E.* ; Picco, P.* ; Doneda, P.* ; Fiorillo, C.* ; Issa, M.Y.* ; Alassiri, A.* ; Alahmad, A.* ; Gerard, A.* ; Liu, P.* ; Yang, Y.* ; Ertl-Wagner, B.* ; Kranz, P.G.* ; Wentzensen, I.M.* ; Stucka, R.* ; Stong, N.* ; Allen, A.S.* ; Goldstein, D.B.* ; Undiagnosed Diseases Network* ; Schoser, B.* ; Rösler, K.M.* ; Alfadhel, M.* ; Capra, V.* ; Chrast, R.* ; Strom, T.M. ; Kamsteeg, E.J.* ; Bönnemann, C.G.* ; Gleeson, J.G.* ; Martini, R.* ; Janke, C.* ; Senderek, J.*

Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

EMBO J. 37:e100540 (2018)
Verlagsversion DOI PMC
Free by publisher
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Cerebellum ; Cytosolic Carboxypeptidase 1 (ccp1/agtpbp1/nna1) ; Motor Neuron ; Neurodegeneration ; Tubulin Polyglutamylation
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Zeitschrift EMBO Journal, The
Quellenangaben Band: 37, Heft: 23, Seiten: , Artikelnummer: e100540 Supplement: ,
Verlag Wiley
Verlagsort Heidelberg, Germany
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)