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Polyglutamylation of microtubules drives neuronal remodeling

Author

Listed:
  • Antoneta Gavoci

    (Technical University of Munich)

  • Anxhela Zhiti

    (Technical University of Munich)

  • Michaela Rusková

    (Institute of Physiology of the Czech Academy of Sciences
    Charles University)

  • Maria M. Magiera

    (Université PSL
    Université Paris-Saclay)

  • Mengzhe Wang

    (Technical University of Munich)

  • Karin A. Ziegler

    (Technical University of Munich
    Partner Site Munich Heart Alliance)

  • Torben J. Hausrat

    (University Medical Center Hamburg-Eppendorf)

  • Anselm I. Ugwuja

    (Technical University of Munich)

  • Shreyangi Chakraborty

    (Université PSL
    Université Paris-Saclay)

  • Stefan Engelhardt

    (Technical University of Munich
    Partner Site Munich Heart Alliance)

  • Matthias Kneussel

    (University Medical Center Hamburg-Eppendorf)

  • Martin Balastik

    (Institute of Physiology of the Czech Academy of Sciences)

  • Carsten Janke

    (Université PSL
    Université Paris-Saclay)

  • Thomas Misgeld

    (Technical University of Munich
    German Center for Neurodegenerative Diseases (DZNE)
    Munich Cluster of Systems Neurology (SyNergy))

  • Monika S. Brill

    (Technical University of Munich
    Munich Cluster of Systems Neurology (SyNergy))

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.

Suggested Citation

  • 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 Kn, 2025. "Polyglutamylation of microtubules drives neuronal remodeling," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60855-6
    DOI: 10.1038/s41467-025-60855-6
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    References listed on IDEAS

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    1. Tatjana Kleele & Petar Marinković & Philip R. Williams & Sina Stern & Emily E. Weigand & Peter Engerer & Ronald Naumann & Jana Hartmann & Rosa M. Karl & Frank Bradke & Derron Bishop & Jochen Herms & A, 2014. "An assay to image neuronal microtubule dynamics in mice," Nature Communications, Nature, vol. 5(1), pages 1-10, December.
    2. Cagla Eroglu & Ben A. Barres, 2010. "Regulation of synaptic connectivity by glia," Nature, Nature, vol. 468(7321), pages 223-231, November.
    3. Torben Johann Hausrat & Philipp C. Janiesch & Petra Breiden & David Lutz & Sabine Hoffmeister-Ullerich & Irm Hermans-Borgmeyer & Antonio Virgilio Failla & Matthias Kneussel, 2022. "Disruption of tubulin-alpha4a polyglutamylation prevents aggregation of hyper-phosphorylated tau and microglia activation in mice," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
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