Journal Article

DZNE-2025-00735

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Polyglutamylation of microtubules drives neuronal remodeling.

Gavoci, A. ; Zhiti, A. ; Rusková, M. ; Magiera, M. M. ; Wang, M. ; Ziegler, K. A. ; Hausrat, T. J. ; Ugwuja, A. I. ; Chakraborty, S. ; Engelhardt, S. ; Kneussel, M. ; Balastik, M. ; Janke, C. ; Misgeld, T.DZNE* ; Brill, M. S.

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-60855-6

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.

Keyword(s): Microtubules: metabolism (MeSH) ; Animals (MeSH) ; Tubulin: metabolism (MeSH) ; Peptide Synthases: metabolism (MeSH) ; Peptide Synthases: genetics (MeSH) ; Motor Neurons: metabolism (MeSH) ; Hippocampus: metabolism (MeSH) ; Hippocampus: cytology (MeSH) ; Neuronal Plasticity: physiology (MeSH) ; Synapses: metabolism (MeSH) ; Synaptic Transmission (MeSH) ; Neurons: metabolism (MeSH) ; Polyglutamic Acid: metabolism (MeSH) ; Neuromuscular Junction: metabolism (MeSH) ; Protein Processing, Post-Translational (MeSH) ; Mice (MeSH) ; Spastin: metabolism (MeSH) ; Tubulin ; Peptide Synthases ; tubulin polyglutamylase ; Polyglutamic Acid ; Spastin

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Contributing Institute(s):

1. Neuronal Cell Biology (AG Misgeld)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2025

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