PXD027667

PXD027667 is an original dataset announced via ProteomeXchange.

Title	Beta-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins
Description	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.
HostingRepository	PRIDE
AnnounceDate	2021-11-29
AnnouncementXML	Submission_2021-11-29_06:25:53.549.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alex Montoya
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	3-(carboxamidomethylthio)propanoylated residue; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2021-07-30 03:45:45	ID requested
⏵ 1	2021-11-29 06:25:53	announced

Dataset with its publication pending

submitter keyword: Synuclein, dopaminergic neurons, synapse, vesicles, transgenic mice, dopamine, MPTP toxicity, neurodegenerative disease, Parkinson’s disease, neurotransmitter vesicular uptake, Mouse, LC-MSMS

Dr Holger Kramer
contact affiliation	MRC - London Institute of Medical Sciences
contact email	h.kramer@lms.mrc.ac.uk
lab head
Alex Montoya
contact affiliation	Medical Research Council - London Institute of Medical Sciences
contact email	alex.montoya@lms.mrc.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD027667
     1. Label: PRIDE project
     2. Name: Beta-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins