Dataset Information

α-Synuclein induced cholesterol lowering increases tonic and reduces depolarization-evoked synaptic vesicle recycling and glutamate release.

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.

SUBMITTER: Lazarevic V

PROVIDER: S-EPMC9174203 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

α-Synuclein induced cholesterol lowering increases tonic and reduces depolarization-evoked synaptic vesicle recycling and glutamate release.

Lazarevic Vesna V Yang Yunting Y Paslawski Wojciech W Svenningsson Per P

NPJ Parkinson's disease 20220607 1

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 depolariza ...[more]

PMID: 35672421

Similar Datasets

Project description:Chronic exposure to alcohol produces adaptations within the basolateral amygdala (BLA) that are associated with the development of anxiety-like behaviors during withdrawal. In part, these adaptations are mediated by plasticity in glutamatergic synapses occurring through an AMPA receptor mediated form of post-synaptic facilitation in addition to a unique form of presynaptic facilitation. In comparison to the post-synaptic compartment, relatively less is understood about the mechanisms involved in the acute and chronic effects of ethanol in the presynaptic terminal. Previous research has demonstrated that glutamatergic terminals in the mouse BLA are sensitive to ethanol mediated inhibition of synaptic vesicle recycling in a strain-dependent fashion. Importantly, the strain-dependent differences in presynaptic ethanol sensitivity are in accordance with known strain-dependent differences in ethanol/anxiety interactions. In the present study, we have used a short-hairpin RNA to knockdown the expression of the presynaptic Munc13-2 protein in C57BL/6J mice, whose BLA glutamate terminals are normally ethanol-insensitive. We injected this shRNA, or a scrambled control virus, into the medial prefrontal cortex (mPFC) which sends dense projections to the BLA. Accordingly, this knockdown strategy reduces the expression of the Munc13-2 isoform in mPFC terminals within the BLA and alters presynaptic terminal function in C57BL/6J mice in a manner that phenocopies DBA/2J glutamate terminals which are normally ethanol-sensitive. Here, we provide evidence that manipulation of this single protein, Munc13-2, renders C57BL/6J terminals sensitive to ethanol mediated inhibition of synaptic vesicle recycling and post-tetanic potentiation. Furthermore, we found that this ethanol inhibition was dose dependent. Considering the important role of Munc13 proteins in synaptic plasticity, this study potentially identifies a molecular mechanism regulating the acute presynaptic effects of ethanol to the long lasting adaptations in the BLA that occur during chronic ethanol exposure.

Dataset Information

α-Synuclein induced cholesterol lowering increases tonic and reduces depolarization-evoked synaptic vesicle recycling and glutamate release.

Publications

α-Synuclein induced cholesterol lowering increases tonic and reduces depolarization-evoked synaptic vesicle recycling and glutamate release.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets