title: Exposure to long chain polyunsaturated fatty acids triggers rapid multimerization of synucleins.
abstract: Detergent-stable multimers of alpha-synuclein have been found specifically in the brains of patients with Parkinson's disease and other neurodegenerative diseases. Here we show that recombinant alpha-synuclein forms multimers in vitro upon exposure to vesicles containing certain polyunsaturated fatty acid (PUFA) acyl groups, including arachidonoyl and docosahexaenoyl. This process occurs at physiological concentrations and much faster than in aqueous solution. PUFA-induced aggregation involves physical association with the vesicle surface via the large apolipoprotein-like lipid-binding domain that constitutes the majority of the protein. beta- and gamma-synucleins, as well as the Parkinson's disease-associated alpha-synuclein variants A30P and A53T, show similar tendencies to multimerize in the presence of PUFAs. Multimerization does not require the presence of any tyrosine residues in the sequence. The membrane-based interaction of the synucleins with specific long chain polyunsaturated phospholipids may be relevant to the protein family's physiological functions and may also contribute to the aggregation of alpha-synuclein observed in neurodegenerative disease.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois 61801, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Perrin
authors.forename: W S
authors.initials: WS
authors.lastname: Woods
authors.forename: D F
authors.initials: DF
authors.lastname: Clayton
authors.forename: J M
authors.initials: JM
authors.lastname: George
mesh_terms: D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D010743:Phospholipids / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry; D051843:Synucleins; D051844:alpha-Synuclein
chemical_list: D005231:Fatty Acids, Unsaturated; D009419:Nerve Tissue Proteins; D010743:Phospholipids; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein