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

ABSTRACT: Previous studies demonstrated that dopaminergic neurons in the substantia nigra pars compacta (SNpc) of mice with null mutations for genes encoding a-synuclein and/or y-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 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, b-synuclein. Dopaminergic neurons of mice lacking b-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 a/b/y-synuclein deficient mice was significantly reduced, while reintroduction of b-synuclein either in vivo or in vitro reversed this effect. Proteomic analysis of complexes formed on the surface of synuclein-free synaptic vesicles after addition of recombinant b-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). Therefore, b-synuclein plays a scaffolding role for the assembly of molecular complexes that enhance the ability of synaptic vesicles to uptake and sequester dopamine and other structurally similar molecules, including MPP+. Deficiency of b-synuclein therefore results in the accumulation of MPP+ in the cytosol, where it imposes a damaging effect on presynaptic terminals and ultimately the destruction of dopaminergic neurons.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Synaptic Membrane

DISEASE(S): Synucleinopathy,Parkinson's Disease

SUBMITTER: Alex Montoya  

LAB HEAD: Dr Holger Kramer

PROVIDER: PXD027667 | Pride | 2021-11-29

REPOSITORIES: Pride