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This study reveals that alpha-synuclein protein regulates dopamine release at nerve terminals by controlling the formation of new microtubules in response to neuronal activity. The researchers found that when alpha-synuclein is phosphorylated at a specific site (serine 129), it binds to tubulin proteins and triggers microtubule nucleation at presynaptic sites, which is essential for transporting synaptic vesicles between boutons and maintaining dopamine release during high neuronal activity. This mechanism was demonstrated through live imaging of cultured dopaminergic neurons, showing that disruption of this process impairs sustained neurotransmitter release.
Why it matters
This discovery provides a molecular explanation for how alpha-synuclein dysfunction may contribute to dopaminergic deficits in Parkinson's disease and related synucleinopathies, where abnormal phosphorylation of this protein accumulates. Understanding this mechanism could lead to new therapeutic targets for treating neurodegenerative diseases characterized by dopamine dysfunction.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.