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DOI 10.15252/embj.2018100540

Медицинская библиотека · The EMBO journal · 2018

Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

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, Guzmán-Vega 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, Ertl-Wagner Birgit, Kranz Peter G, Wentzensen Ingrid M, Stucka Rolf, Stong Nicholas, Allen Andrew S, Goldstein David B, Undiagnosed Diseases Network, 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

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПеревод пока не подготовлен

Аннотация

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.

Для цитирования: 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, Guzmán-Vega 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, Ertl-Wagner Birgit, Kranz Peter G, Wentzensen Ingrid M, Stucka Rolf, Stong Nicholas, Allen Andrew S, Goldstein David B, Undiagnosed Diseases Network, 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. Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.. The EMBO journal. 2018. DOI: 10.15252/embj.2018100540.

Предметные рубрики MeSH

CarboxypeptidasesCerebellumFemaleGTP-Binding ProteinsHumansMaleMotor NeuronsPeptidesPeripheral NervesProtein Processing, Post-TranslationalPurkinje CellsSerine-Type D-Ala-D-Ala CarboxypeptidaseSpineSpinocerebellar Degenerations
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