α-Synuclein and γ-Tubulin Cooperatively Regulate Activity-Evoked Presynaptic Microtubule Nucleation to Gate Dopamine Release

Authors

Comincini, A., Choi, S. J., Mosharov, E., Milanetti, E., Kanter, E., Ruocco, G., Cappelletti, G., Sulzer, D. L., Bartolini, F.

Abstract

alpha-Synuclein has long been implicated in the regulation of synaptic activity, but the molecular basis that underlies this function has been elusive. Here, we identify a microtubule (MT)-dependent mechanism through which alpha-synuclein regulates synaptic dopamine release. Using live imaging of cultured dopaminergic neurons, we visualize dynamic MTs at individual presynaptic boutons and show that neuronal activity triggers local gamma-tubulin-dependent MT nucleation. We find that this nucleation is essential for interbouton synaptic vesicle (SV) transport and for sustained dopamine release during high activity. We further discover that alpha-synuclein acts as a positive regulator of presynaptic MT nucleation by binding directly to gamma-tubulin and the alpha/beta-tubulin heterodimer. Activity-evoked phosphorylation of alpha-synuclein at serine 129, a modification that accumulates in synucleinopathies and a molecular switch for alpha-synuclein binding to synaptic proteins, occurs in the region of alpha/beta- tubulin binding and is both necessary and sufficient for MT initiation. Our findings reveal a previously unrecognized, activity-dependent role for alpha-synuclein in the nucleation of axonal MTs that enables on-demand SV interbouton redistribution and dopamine release. This mechanism provides a novel molecular link between alpha-synuclein phosphorylation and MT-dependent modulation of dopamine release, offering insight into how its dysregulation may contribute to dopaminergic synaptic dysfunction, a central feature of synucleinopathies.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 05 Jun 2026.

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