Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport

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.

Loss of tubulin deglutamylase CCP 1 causes infantile‐onset neurodegeneration

“…While the CCP1-associated human disease reported here represents a rare monogenic condition, dysregulation of tubulin polyglutamylation could also be involved in other neurodegenerative disorders. In a manuscript appearing in the same issue of this journal, Magiera and colleagues recognized neurodegeneration as a general response to impaired tubulin deglutamylation in mice with global ablation of neuronal deglutamylases activity (Magiera et al, 2018). In their manuscript, Magiera et al pinpointed a potential disease mechanism in tubulin deglutamylase-deficient neurons: They observed disturbed axonal transport, A Absent (A1, B1) or low-level CCP1 (D1) in patient-derived skin fibroblasts.…”

“…Finally, the discovery of CCP1 deficiency as a cause of human neurodegeneration also entails a promising perspective that these disorders could become therapeutically accessible. Notably, Purkinje cell degeneration in pcd mice can be halted by counterbalancing tubulin glutamylation by genetic approaches (Rogowski et al, 2010;Berezniuk et al, 2012;Magiera et al, 2018). Since PTMs and their modifying enzymes are accessible targets for drug development (Huq & Wei, 2007), agents specifically modulating levels of tubulin polyglutamylation will probably soon become available.…”

“…It is tempting to speculate that dysregulation of tubulin glutamylation could be a so-far unrecognized risk factor that accelerates neuronal death in conjunction with other influences over the long life span of A Cerebellar atrophy in pcd mice. Notably, Purkinje cell degeneration in pcd mice can be halted by counterbalancing tubulin glutamylation by genetic approaches (Rogowski et al, 2010;Berezniuk et al, 2012;Magiera et al, 2018). Scale bar, 500 lm.…”

“…Samples were run on 10% SDS-PAGE gels under conditions allowing separation of aand b-tubulins (TUB gels) (Magiera & Janke, 2013) and blotted onto nitrocellulose membranes. Deep-frozen human muscle biopsy specimens (M. quadriceps) from individual B1 and controls were homogenized with a rotor-stator homogenizer in 10 mM Tris, pH 7.4 containing 1% SDS.…”

Genetically encoded live cell sensor for tyrosinated microtubules

“…A key regulatory process that governs microtubule interaction with its cognate proteins is the diversity of tubulin genes and post-translational modifications (PTMs) (Janke, 2014). Most of the PTMs are reversible and defects in these PTM enzymes leads to abnormal levels of microtubule modifications, manifested in different disease pathologies (Magiera et al, 2018a) causing neurodegeneration (Magiera et al, 2018b) and cardiomyopathies (Chen et al, 2018;Robison et al, 2016).…”