Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport

  • Maria M Magiera
  • Satish Bodakuntla
  • Jakub Žiak
  • Sabrina Lacomme
  • Patricia Marques Sousa
  • Sophie Leboucher
  • Torben J Hausrat
  • Christophe Bosc
  • Annie Andrieux
  • Matthias Kneussel
  • Marc Landry
  • André Calas
  • Martin Balastik
  • Carsten Janke

Abstract

Posttranslational modifications of tubulin are emerging regulators of microtubule functions. We have shown earlier that upregulated polyglutamylation is linked to rapid degeneration of Purkinje cells in mice with a mutation in the deglutamylating enzyme CCP1. How polyglutamylation leads to degeneration, whether it affects multiple neuron types, or which physiological processes it regulates in healthy neurons has remained unknown. Here, we demonstrate that excessive polyglutamylation induces neurodegeneration in a cell-autonomous manner and can occur in many parts of the central nervous system. Degeneration of selected neurons in CCP1-deficient mice can be fully rescued by simultaneous knockout of the counteracting polyglutamylase TTLL1. Excessive polyglutamylation reduces the efficiency of neuronal transport in cultured hippocampal neurons, suggesting that impaired cargo transport plays an important role in the observed degenerative phenotypes. We thus establish polyglutamylation as a cell-autonomous mechanism for neurodegeneration that might be therapeutically accessible through manipulation of the enzymes that control this posttranslational modification.

Bibliographical data

Original languageEnglish
ISSN0261-4189
DOIs
Publication statusPublished - 03.12.2018
PubMed 30420556