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.

Bordeaux Imaging Center BIC UMS 3420 Université Bordeaux Bordeaux France

Center for Molecular Neurobiology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Molecular Neurobiology Institute of Physiology Czech Academy of Sciences Prague 4 Czech Republic

Faculty of Science Charles University Prague 2 Czech Republic

Grenoble Institut des Neurosciences GIN Université Grenoble Alpes Grenoble France

Inserm U1216 Grenoble France

Institut Curie CNRS UMR3348 PSL Research University Orsay France

Interdisciplinary Institute for Neuroscience CNRS UMR5297 Université Bordeaux Bordeaux France

Université Paris Saclay CNRS UMR3348 Université Paris Sud Orsay France

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Nat Rev Mol Cell Biol. 2019 Jan;20(1):1. doi: 10.1038/s41580-018-0083-1. PubMed

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Curr Biol. 2019 Jan 7;29(1):R28-R30. doi: 10.1016/j.cub.2018.11.031. PubMed

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Tubulin polyglutamylation differentially regulates microtubule-interacting proteins

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