Polyglutamylation of microtubules drives neuronal remodeling

Antoneta Gavoci, Anxhela Zhiti, Michaela Rusková, Maria M. Magiera, Mengzhe Wang, Karin A. Ziegler, Torben J. Hausrat, Anselm I. Ugwuja, Shreyangi Chakraborty, Stefan Engelhardt, Matthias Kneussel, Martin Balastik, Carsten Janke, Thomas Misgeld and Monika S. Brill ()
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Antoneta Gavoci: Technical University of Munich
Anxhela Zhiti: Technical University of Munich
Michaela Rusková: Institute of Physiology of the Czech Academy of Sciences
Maria M. Magiera: Université PSL
Mengzhe Wang: Technical University of Munich
Karin A. Ziegler: Technical University of Munich
Torben J. Hausrat: University Medical Center Hamburg-Eppendorf
Anselm I. Ugwuja: Technical University of Munich
Shreyangi Chakraborty: Université PSL
Stefan Engelhardt: Technical University of Munich
Matthias Kneussel: University Medical Center Hamburg-Eppendorf
Martin Balastik: Institute of Physiology of the Czech Academy of Sciences
Carsten Janke: Université PSL
Thomas Misgeld: Technical University of Munich
Monika S. Brill: Technical University of Munich

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Developmental remodeling shapes neural circuits via activity-dependent pruning of synapses and axons. Regulation of the cytoskeleton is critical for this process, as microtubule loss via enzymatic severing is an early step of pruning across many circuits and species. However, how microtubule-severing enzymes, such as spastin, are activated in specific neuronal compartments remains unknown. Here, we reveal that polyglutamylation, a post-translational tubulin modification enriched in neurons, plays an instructive role in developmental remodeling by tagging microtubules for severing. Motor neuron-specific gene deletion of enzymes that add or remove tubulin polyglutamylation—TTLL glutamylases vs. CCP deglutamylases—accelerates or delays neuromuscular synapse remodeling in a neurotransmission-dependent manner. This mechanism is not specific to peripheral synapses but also operates in central circuits, e.g., the hippocampus. Thus, tubulin polyglutamylation acts as a cytoskeletal rheostat of remodeling that shapes neuronal morphology and connectivity.

Date: 2025
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DOI: 10.1038/s41467-025-60855-6

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