Journal
EMBO JOURNAL
Volume 37, Issue 23, Pages -Publisher
WILEY
DOI: 10.15252/embj.2018100440
Keywords
axonal transport; neurodegeneration; tubulin code; tubulin polyglutamylation; tubulin posttranslational modifications
Categories
Funding
- program Investissements d'Avenir [ANR-10-LBX-0038, ANR-10-IDEX-0001-02 PSL]
- Institut Curie
- French National Research Agency (ANR) [ANR-12-BSV2-0007]
- Institut National du Cancer (INCA) [2013-1-PL BIO-02-ICR-1, 2014-PL BIO-11-ICR-1]
- Fondation pour la Recherche Medicale (FRM) [DEQ20170336756]
- EMBO short-term fellowship [ASTF 148-2015]
- Fondation Vaincre Alzheimer grant [FR-16055p]
- Grant Agency of the Charles University [682217]
- Czech science foundation grant [16-15915S]
- European Regional Development Fund project, OPPK Mikroskopicky system [CZ.2.16/3.1.00/28034]
- German Research Foundation [DFG-KN556/11-1]
- CNRS
- French National Research Agency through the Investissment for the future program (France-BioImaging) [ANR-10-INSB-04]
- Marie Curie FP7-PEOPLE-2012-CIG grant [334431]
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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.
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