Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration

Undiagnosed Diseases Network

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalEMBO Journal
Volume37
Issue number23
DOIs
Publication statusPublished - Dec 3 2018

Fingerprint Dive into the research topics of 'Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration'. Together they form a unique fingerprint.

  • Cite this