Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

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.

• Authors: Vandana Shashi, Maria M Magiera, Dennis Klein, Maha Zaki, Kelly Schoch, Sabine Rudnik-Schöneborn, Andrew Norman, Osorio Lopes Abath Neto, Marina Dusl, Xidi Yuan, Luca Bartesaghi, Patrizia De Marco, Ahmed A Alfares, Ronit Marom, Stefan T Arold, Francisco J Guzmán-Vega, Loren Dm Pena, Edward C Smith, Maja Steinlin, Mohamed Oe Babiker, Payam Mohassel, A Reghan Foley, Sandra Donkervoort, Rupleen Kaur, Partha S Ghosh, Valentina Stanley, Damir Musaev, Caroline Nava, Cyril Mignot, Boris Keren, Marcello Scala, Elisa Tassano, Paolo Picco, Paola Doneda, Chiara Fiorillo, Mahmoud Y Issa, Ali Alassiri, Ahmed Alahmad, Amanda Gerard, Pengfei Liu, Yaping Yang, Birgit Ertl-Wagner, Peter G Kranz, Ingrid M Wentzensen, Rolf Stucka, Nicholas Stong, Andrew S Allen, David B Goldstein, Undiagnosed Diseases Network, Benedikt Schoser, Kai M Rösler, Majid Alfadhel, Valeria Capra, Roman Chrast, Tim M Strom, Erik-Jan Kamsteeg, Carsten G Bönnemann, Joseph G Gleeson, Rudolf Martini, Carsten Janke, Jan Senderek
• Journal: The EMBO journal (EMBO J) Vol. 37 Issue 23 (12 03 2018) ISSN: 1460-2075 [Electronic] England
• PMID: 30420557 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors.

Chemical References

• Peptides
• polyglutamine
• Carboxypeptidases
• AGTPBP1 protein, human
• Serine-Type D-Ala-D-Ala Carboxypeptidase
• GTP-Binding Proteins

Topics

• Carboxypeptidases (deficiency)
• Cerebellum (enzymology, pathology)
• Female
• GTP-Binding Proteins
• Humans
• Male
• Motor Neurons (enzymology, pathology)
• Peptides (genetics, metabolism)
• Peripheral Nerves (enzymology, pathology)
• Protein Processing, Post-Translational
• Purkinje Cells (enzymology, pathology)
• Serine-Type D-Ala-D-Ala Carboxypeptidase
• Spine (enzymology, pathology)
• Spinocerebellar Degenerations (enzymology, genetics, pathology)