TY  - JOUR
AU  - Gavoci, Antoneta
AU  - Zhiti, Anxhela
AU  - Rusková, Michaela
AU  - Magiera, Maria M
AU  - Wang, Mengzhe
AU  - Ziegler, Karin A
AU  - Hausrat, Torben J
AU  - Ugwuja, Anselm I
AU  - Chakraborty, Shreyangi
AU  - Engelhardt, Stefan
AU  - Kneussel, Matthias
AU  - Balastik, Martin
AU  - Janke, Carsten
AU  - Misgeld, Thomas
AU  - Brill, Monika S
TI  - Polyglutamylation of microtubules drives neuronal remodeling.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2025-00735
SP  - 5384
PY  - 2025
AB  - 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.
KW  - Microtubules: metabolism
KW  - Animals
KW  - Tubulin: metabolism
KW  - Peptide Synthases: metabolism
KW  - Peptide Synthases: genetics
KW  - Motor Neurons: metabolism
KW  - Hippocampus: metabolism
KW  - Hippocampus: cytology
KW  - Neuronal Plasticity: physiology
KW  - Synapses: metabolism
KW  - Synaptic Transmission
KW  - Neurons: metabolism
KW  - Polyglutamic Acid: metabolism
KW  - Neuromuscular Junction: metabolism
KW  - Protein Processing, Post-Translational
KW  - Mice
KW  - Spastin: metabolism
KW  - Tubulin (NLM Chemicals)
KW  - Peptide Synthases (NLM Chemicals)
KW  - tubulin polyglutamylase (NLM Chemicals)
KW  - Polyglutamic Acid (NLM Chemicals)
KW  - Spastin (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40562742
C2  - pmc:PMC12198417
DO  - DOI:10.1038/s41467-025-60855-6
UR  - https://pub.dzne.de/record/279358
ER  -