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<jats:title>Abstract</jats:title> <jats:p>Background. Previous studies demonstrated that dopaminergic neurons in the substantia nigra pars compacta (SNpc) of mice with null mutations for genes encoding α-synuclein and/or γ-synuclein are resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. An original straightforward interpretation of these results was that these proteins are directly involved in the mechanism of MPTP-induced degeneration and this view has become commonly accepted. Here we provide evidence that a plausible alternative explanation of this resistance is not the absence of these synucleins per se but their substitution on the membrane of synaptic vesicles by the third member of the family, β-synuclein. Methods. An effect of sub-chronic MPTP regimen on dopaminergic neurons of SNpc was studied in mice lacking members of the synuclein family in all possible combinations. Dopamine uptake was assessed in synaptic vesicles isolated from synuclein null mutant mice. Protein composition of synaptic vesicles was studied by mass spectrometry. Results. Dopaminergic neurons of mice lacking β-synuclein singularly or in combination with the loss of other synucleins, were sensitive to the toxic effect of MPTP. Dopamine uptake by synaptic vesicles isolated from the striatum of triple α/β/γ-synuclein deficient mice was significantly reduced, while reintroduction of β-synuclein either <jats:italic>in vivo</jats:italic> or <jats:italic>in vitro</jats:italic> reversed this effect. Proteomic analysis of complexes formed on the surface of synuclein-free synaptic vesicles after addition of recombinant β-synuclein identified multiple integral constituents of these vesicles as well as typically cytosolic proteins, including key enzymes involved in dopamine synthesis, tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC). Conclusions. Of the three members of the synuclein family, only β-synuclein can play a scaffolding role for the assembly of molecular complexes that potentiate the ability of synaptic vesicles to uptake and sequester dopamine and other structurally similar molecules, including 1-methyl-4-phenylpyridinium (MPP<jats:sup>+</jats:sup>), a toxic metabolite of MPTP. The increased presence and activity of β-synuclein at the synaptic vesicles, and not the absence of other synucleins per se, explains the decreased sensitivity to MPTP toxicity of SNpc dopaminergic neurons in mice lacking α-synuclein and/or γ-synuclein.</jats:p>

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