Abstract
Synucleins, a family of three proteins highly expressed in neurons, are predominantly known for the direct involvement of α-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 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–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-synuclein 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 to subchronic administration of the Parkinson's disease–inducing prodrug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 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 versus 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, a toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which would explain why dopaminergic neurons expressing β-synuclein and lacking α-synuclein and/or γ-synuclein are resistant to this neurotoxin.
Highlights
We showed that the resistance of dopaminergic neurons of the substantia nigra pars compacta (SNpc) to subchronic administration of the Parkinson’s diseaseinducing prodrug 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)
-synuclein The sensitivity of dopaminergic neurons to MPTP depends on the ability of its active toxic metabolite, MPP+, to enter the cell via the dopamine transporter (DAT) and to avoid being sequestered in synaptic vesicles by a vesicular monoamine transporter (VMAT-2)-driven mechanism [22,23,24]
We have previously demonstrated that the function of DAT in synapses of SNpc neurons is not affected by the absence of either - and synucleins or all three synucleins [25,26]
Summary
We demonstrated that the vesicular monoamine transporter 2 (VMAT2)-dependent dopamine uptake by synaptic vesicles isolated from the striatum of mice lacking -synuclein is significantly reduced. Morphometric analysis of the number of TH-positive neurons in the SNpc of wild type (WT) and TKO mice treated with a subchronic with the well-documented ability of synucleins to interact with various biological and synthetic membranes, with high curvature vesicles [27,28,29], we showed that all three family members are present in the synaptic vesicle fraction despite being reduction) were compared, suggesting that predominantly cytosolic proteins in the the effect is not age- or sex-dependent.
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