Reduced tubulin polyglutamylation perturbs neuronal function and causes late-onset neurodegeneration

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Abstract Microtubules are essential for neuronal functions and are involved in many neurodegenerative disorders. A posttranslational modification (PTM) of neuronal microtubules, polyglutamylation, was shown to control cargo transport and induce early-onset neurodegeneration when excessively accumulated. To determine the physiological importance of this PTM, we characterised mouse models with reduced polyglutamylation. We demonstrate that these mice develop late-onset atrophy of the olfactory bulb and frontal cortex, progressively reduced dendritic spine density, and deficits in olfaction, memory, and learning. This indicates an important role of polyglutamylation in neuronal function. To test whether the observed late-onset neurodegeneration is linked to Tau pathology, we combined mice with reduced polyglutamylation with the transgenic Tau P301S model for tauopathy. Strikingly, reduced polyglutamylation accelerated the most characteristic phenotype in the tauopathic mice – their premature demise. Our work reveals key roles of microtubule polyglutamylation in neuronal function with implications in late-onset neurodegeneration linked to Tau pathology.

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