Reduced Microtubule Polyglutamylation Perturbs Neuronal Function and Accelerates Tau-Induced Neurodegeneration

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.

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BibTeX RIS

BibTeX

@misc{chakraborty2026reduced,
  title = {{Reduced Microtubule Polyglutamylation Perturbs Neuronal Function and Accelerates Tau-Induced Neurodegeneration}},
  author = {Shreyangi Chakraborty and Silvia Poggini and Michaela Rusková and Isabelle Lavenir and Davide Boido and Adela Karhanova and Laetitia Besse and Naomi Ciano Albanese and Yana Al-Inaya and Laura Lebrun and Veronique Henriot and Zdenek Lansky and Michel Goedert and Luisa Ciobanu and Martin Balastik and Igor Branchi and Carsten Janke and Maria M Magiera},
  howpublished = {HAL},
  year = {2026},
  month = jul,
  doi = {10.64898/2026.07.31.742027},
  url = {https://hal.science/hal-05779720v1},
  note = {CC BY 4.0},
}

RIS

TY  - UNPB
TI  - Reduced Microtubule Polyglutamylation Perturbs Neuronal Function and Accelerates Tau-Induced Neurodegeneration
AU  - Shreyangi Chakraborty
AU  - Silvia Poggini
AU  - Michaela Rusková
AU  - Isabelle Lavenir
AU  - Davide Boido
AU  - Adela Karhanova
AU  - Laetitia Besse
AU  - Naomi Ciano Albanese
AU  - Yana Al-Inaya
AU  - Laura Lebrun
AU  - Veronique Henriot
AU  - Zdenek Lansky
AU  - Michel Goedert
AU  - Luisa Ciobanu
AU  - Martin Balastik
AU  - Igor Branchi
AU  - Carsten Janke
AU  - Maria M Magiera
PY  - 2026
DA  - 2026/07/31
PB  - HAL
DO  - 10.64898/2026.07.31.742027
UR  - https://hal.science/hal-05779720v1
AB  - 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.
ER  -

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