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Loss of tubulin deglutamylase CCP 1 causes infantile‐onset neurodegeneration
Author(s) -
Shashi Vandana,
Magiera Maria M,
Klein Dennis,
Zaki Maha,
Schoch Kelly,
RudnikSchöneborn Sabine,
Norman Andrew,
Lopes Abath Neto Osorio,
Dusl Marina,
Yuan Xidi,
Bartesaghi Luca,
De Marco Patrizia,
Alfares Ahmed A,
Marom Ronit,
Arold Stefan T,
GuzmánVega Francisco J,
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,
ErtlWagner 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 ErikJan,
Bönnemann Carsten G,
Gleeson Joseph G,
Martini Rudolf,
Janke Carsten,
Senderek Jan
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2018100540
Subject(s) - neurodegeneration , tubulin , biology , neuroscience , cerebellum , huntington's disease , motor neuron , spinal muscular atrophy , microtubule , microbiology and biotechnology , pathology , disease , medicine , gene , spinal cord , genetics
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 CCP 1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP 1 in 13 individuals with infantile‐onset neurodegeneration and confirmed the absence of functional CCP 1 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.