Synaptic vesicle glycoprotein 2C enhances vesicular storage of dopamine and counters dopaminergic toxicitySynaptic vesicle glycoprotein 2C enhances vesicular storage of dopamine and counters dopaminergic toxicity

Abstract

Dopaminergic neurons of the substantia nigra exist in a persistent state of vulnerability resulting from high baseline oxidative stress, high-energy demand, and broad unmyelinated axonal arborisations. Impairments in the storage of dopamine compound this stress because of cytosolic reactions that transform the vital neurotransmitter into an endogenous neurotoxicant, and this toxicity is thought to contribute to the dopamine neuron degeneration that occurs Parkinson's disease. We have previously identified synaptic vesicle glycoprotein 2C (SV2C) as a modifier of vesicular dopamine function, demonstrating that genetic ablation of SV2C in mice results in decreased dopamine content and evoked dopamine release in the striatum. Here, we adapted a previously published in vitro assay utilising false fluorescent neurotransmitter 206 (FFN206) to visualise how SV2C regulates vesicular dopamine dynamics and determined that SV2C promotes the uptake and retention of FFN206 within vesicles. In addition, we present data indicating that SV2C enhances the retention of dopamine in the vesicular compartment with radiolabelled dopamine in vesicles isolated from immortalised cells and from mouse brain. Further, we demonstrate that SV2C enhances the ability of vesicles to store the neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) and that genetic ablation of SV2C results in enhanced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced vulnerability in mice. Together, these findings suggest that SV2C functions to enhance vesicular storage of dopamine and neurotoxicants and helps maintain the integrity of dopaminergic neurons.

Publisher

Wiley

Publication Date

5-1-2024

Publication Title

European Journal of Neuroscience

Department

Neuroscience

Document Type

Article

DOI

https://doi.org/10.1111/ejn.16311

Notes

Special issue.

Keywords

MPP+, MPTP, Parkinson's disease, SV2C, VMAT2, dopamine, retention, synaptic glycoprotein 2C, vesicle, vesicular monoamine transporter 2

Language

English

Format

text

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