α-Synuclein Induced Cholesterol Lowering Increases Tonic and Reduces Depolarization-evoked Synaptic Vesicle Recycling and Glutamate Release

Overview

Journal NPJ Parkinsons Dis

Date 2022 Jun 7

PMID 35672421

Authors

Vesna Lazarevic

Yunting Yang

Wojciech Paslawski

Per Svenningsson

Affiliations

Soon will be listed here.

Abstract

α-Synuclein (α-syn) is a key molecule linked to Parkinson's disease pathology. Physiologically, the monomeric α-syn in the presynaptic termini is involved in regulation of neurotransmission, but the pathophysiology of extracellular monomeric α-syn is still unknown. Utilizing both in vivo and in vitro approaches, we investigated how extracellular α-syn impact presynaptic structure and function. Our data revealed that treatment with exogenous α-syn leads to increased tonic and decreased depolarization-evoked synaptic vesicle (SV) recycling and glutamate release. This was associated with mobilization of molecularly distinct SV pools and reorganization of active zone components. Our study also showed that exogenous α-syn impaired neuronal cholesterol level and that the cholesterol binding domain of α-syn was sufficient to exert the same presynaptic phenotype as the full-length protein. The present study sheds new light on physiological functions of extracellular α-syn in overall maintenance of presynaptic activity that involves the reorganization of both presynaptic compartment and cholesterol-rich plasma membrane domains.

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