β-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins

Ninkina, Natalia ORCID: https://orcid.org/0000-0001-8570-5648, Millership, Steven J., Peters, Owen M. ORCID: https://orcid.org/0000-0002-6824-0663, Connor-Robson, Natalie ORCID: https://orcid.org/0000-0001-8350-6928, Chaprov, Kirill, Kopylov, Arthur T., Montoya, Alex, Kramer, Holger, Withers, Dominic J. and Buchman, Vladimir L. ORCID: https://orcid.org/0000-0002-7631-8352 2021. β-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins. Journal of Biological Chemistry 297 (6) , 101375. 10.1016/j.jbc.2021.101375

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Abstract

Synucleins, a family of three proteins highly expressed in neurons, are predominantly known for the direct involvement of α-synuclein in the aetiology and pathogenesis of Parkinson’s and certain other neurodegenerative diseases, but their precise physiological functions are still not fully understood. Previous studies have demonstrated the importance of α-synuclein as a modulator of various mechanisms implicated in chemical neurotransmission, but information concerning the involvement of other synuclein family members, β-synuclein and γ-synuclein, in molecular processes within presynaptic terminals is limited. Here we demonstrated that the vesicular monoamine transporter 2 (VMAT2)-dependent dopamine uptake by synaptic vesicles isolated from the striatum of mice lacking β-synuclein is significantly reduced. Reciprocally, reintroduction, either in vivo or in vitro, of β-synuclein but not α- or γ-synuclein improves uptake by triple α/β/γ-synuclein deficient striatal vesicles. We also showed that the resistance of dopaminergic neurons of the substantia nigra pars compacta (SNpc) to subchronic administration of the Parkinson’s disease-inducing prodrug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) depends on the presence of β-synuclein but only when one or both other synucleins are absent. Furthermore, proteomic analysis of synuclein-deficient synaptic vesicles vs those containing only β-synuclein revealed differences in their protein compositions. We suggest that the observed potentiation of dopamine uptake by β-synuclein might be caused by different protein architecture of the synaptic vesicles. It is also feasible that such structural changes improve synaptic vesicle sequestration of 1-methyl-4-phenylpyridinium (MPP+), a toxic metabolite of MPTP, which would explain why dopaminergic neurons expressing β-synuclein and lacking α-synuclein and/or γ-synuclein are resistant to this neurotoxin.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Funders:	Wellcome Trust
Date of First Compliant Deposit:	8 November 2021
Date of Acceptance:	28 October 2021
Last Modified:	18 May 2023 05:40
URI:	https://orca.cardiff.ac.uk/id/eprint/145257

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