Reduced Microtubule Polyglutamylation Perturbs Neuronal Function and Accelerates Tau-Induced Neurodegeneration
Year: 2026
Type: preprint
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, Tau protein binding to microtubules and to induce early-onset neurodegeneration when exceeding physiological levels. 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 cognitive control. This indicates an important role of polyglutamylation in neuronal function. To test whether the observed defects are linked to neurodegeneration, we combined mice with reduced polyglutamylation with a transgenic model for tauopathy. Strikingly, reduced polyglutamylation accelerated the premature demise of mice transgenic for human Tau carrying the P301S mutation. Our work thus reveals key roles of microtubule polyglutamylation in neuronal function with implications for late-onset neurodegeneration linked to Tau pathology.
Authors: Shreyangi Chakraborty, Silvia Poggini, Michaela Rusková, Isabelle Lavenir, Davide Boido, Adela Karhanova, Laetitia Besse, Naomi Ciano Albanese, Yana Al-Inaya, Laura Lebrun, Veronique Henriot, Zdenek Lansky, Michel Goedert, Luisa Ciobanu, Martin Balastik, Igor Branchi, Carsten Janke, Maria M. Magiera
Institutions: Centre National de la Recherche Scientifique, Inserm, Université Paris Sciences et Lettres, Université Paris-Saclay, Intégrité du génome, ARN et cancer, Institut Curie, Istituto Superiore di Sanità, Czech Academy of Sciences, Charles University, Czech Academy of Sciences, Institute of Physiology, MRC Laboratory of Molecular Biology, Medical Research Council, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, CEA Paris-Saclay, Czech Academy of Sciences, Institute of Biotechnology, Centre d'Imagerie Multimodale
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: Massachusetts General Hospital, Yale University, Biogen, Fondation Vaincre Alzheimer, European Commission, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Ministerstvo Školství, Mládeže a Tělovýchovy, Grantová Agentura České Republiky, Centre National de la Recherche Scientifique, National Tsing Hua University, Université Paris-Saclay, National Institutes of Health, European Regional Development Fund
Awards: G1093144819, G1413419130, G1435997383, G1463346336, National Infrastructure for Biological and Medical Imaging Czech-BioImaging, G1681878798, G176604203, G1935710221, National Infrastructure for Biological and Medical Imaging, Paris Sciences et Lettres, G291036901, G3490171961, G3882170237, G3937102218, G4280972364, G4425616012, G4433258970, G4857714998, G5004758845, G505894138, G5287318854, G5296751580, G5503490858, G5641063287, G5916014575, G591834160, Dissecting axonal transport homeostasis mediated by the tubulin code, Czech Infrastructure for Integrative Structural Biology, G6713506817, G6761430300, G7365613897, G782245399, G803096421, G82516473, G8265045674, G844339007
OpenAlex ID: W7197041368