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

Synucleins, a family of three proteins highly expressed in neurons, are predominantly known for the direct involvement of alpha-synuclein in the etiology 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 alpha-synuclein as a modulator of various mechanisms implicated in chemical neurotransmission, but information concerning the involvement of other synuclein family members, beta-synuclein and gamma-synuclein, in molecular processes within presynaptic terminals is limited. Here, we demonstrated that the vesicular monoamine transporter 2-dependent dopamine uptake by synaptic vesicles isolated from the striatum of mice lacking beta-synuclein is significantly reduced. Reciprocally, reintroduction, either in vivo or in vitro, of beta-synuclein but not alpha-synuclein or gamma-synuclein improves uptake by triple alpha/beta/gamma-synuclein-deficient striatal vesicles. We also showed that the resistance of dopaminergic neurons of the substantia nigra pars compacta to subchronic administration of the Parkinson's disease-inducing prodrug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine depends on the presence of beta-synuclein but only when one or both other synucleins are absent. Furthermore, proteomic analysis of synuclein-deficient synaptic vesicles versus those containing only beta-synuclein revealed differences in their protein compositions. We suggest that the observed potentiation of dopamine uptake by beta-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, a toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which would explain why dopaminergic neurons expressing beta-synuclein and lacking alpha-synuclein and/or gamma-synuclein are resistant to this neurotoxin.