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Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration

Research output: Contribution to journalArticle

  • Undiagnosed Diseases Network
  • 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 D.M. Pena
  • Edward C. Smith
  • Maja Steinlin
  • Mohamed O.E. 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
  • Benedikt Schoser
  • Kai M. Rösler
Original languageEnglish
Article numbere100540
Number of pages12
JournalEMBO Journal
Volume37
Issue number23
Early online date12 Nov 2018
DOIs
DateAccepted/In press - 11 Oct 2018
DateE-pub ahead of print - 12 Nov 2018
DatePublished (current) - 3 Dec 2018

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.

    Research areas

  • cerebellum, cytosolic carboxypeptidase 1 (CCP1/AGTPBP1/NNA1), motor neuron, neurodegeneration, tubulin polyglutamylation

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