title: Alpha-synuclein sequesters arachidonic acid to modulate SNARE-mediated exocytosis.
abstract: Alpha-synuclein is a synaptic modulatory protein implicated in the pathogenesis of Parkinson disease. The precise functions of this small cytosolic protein are still under investigation. alpha-Synuclein has been proposed to regulate soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins involved in vesicle fusion. Interestingly, alpha-synuclein fails to interact with SNARE proteins in conventional protein-binding assays, thus suggesting an indirect mode of action. As the structural and functional properties of both alpha-synuclein and the SNARE proteins can be modified by arachidonic acid, a common lipid regulator, we analysed this possible tripartite link in detail. Here, we show that the ability of arachidonic acid to stimulate SNARE complex formation and exocytosis can be controlled by alpha-synuclein, both in vitro and in vivo. Alpha-synuclein sequesters arachidonic acid and thereby blocks the activation of SNAREs. Our data provide mechanistic insights into the action of alpha-synuclein in the modulation of neurotransmission.
authors.affiliation: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Darios
authors.forename: Violeta
authors.initials: V
authors.lastname: Ruipérez
authors.forename: Inmaculada
authors.initials: I
authors.lastname: López
authors.forename: Jose
authors.initials: J
authors.lastname: Villanueva
authors.forename: Luis M
authors.initials: LM
authors.lastname: Gutierrez
authors.forename: Bazbek
authors.initials: B
authors.lastname: Davletov
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000166:cytology / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016716:PC12 Cells; D051381:Rats; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism; D050827:Syntaxin 1 / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; D051844:alpha-Synuclein; D016718:Arachidonic Acid