title: Dopamine promotes alpha-synuclein aggregation into SDS-resistant soluble oligomers via a distinct folding pathway.
abstract: Dopamine (DA) and alpha-synuclein (alpha-SN) are two key molecules associated with Parkinson's disease (PD). We have identified a novel action of DA in the initial phase of alpha-SN aggregation and demonstrate that DA induces alpha-SN to form soluble, SDS-resistant oligomers. The DA:alpha-SN oligomeric species are not amyloidogenic as they do not react with thioflavin T and lack the typical amyloid fibril structures as visualized with electron microscopy. Circular dichroism studies indicate that in the presence of lipid membranes DA interacts with alpha-SN, causing an alteration to the structure of the protein. Furthermore, DA inhibited the formation of iron-induced alpha-SN amyloidogenic aggregates, suggesting that DA acts as a dominant modulator of alpha-SN aggregation. These observations support the paradigm emerging for other neurodegenerative diseases that the toxic species is represented by a soluble oligomer and not the insoluble fibril.
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria, Australia. r.cappai@unimelb.edu.au
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
authors.forename: Su-Ling
authors.initials: SL
authors.lastname: Leck
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Tew
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Williamson
authors.forename: David P
authors.initials: DP
authors.lastname: Smith
authors.forename: Denise
authors.initials: D
authors.lastname: Galatis
authors.forename: Robyn A
authors.initials: RA
authors.lastname: Sharples
authors.forename: Cyril C
authors.initials: CC
authors.lastname: Curtain
authors.forename: Feda' E
authors.initials: FE
authors.lastname: Ali
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cherny
authors.forename: Janetta G
authors.initials: JG
authors.lastname: Culvenor
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Bottomley
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Hill
mesh_terms: D000682:Amyloid / Q000737:chemistry; D052160:Benzothiazoles; D002942:Circular Dichroism; D004298:Dopamine / Q000494:pharmacology*; D005290:Ferric Compounds / Q000494:pharmacology; D006801:Humans; D010300:Parkinson Disease / Q000209:etiology; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012967:Sodium Dodecyl Sulfate / Q000494:pharmacology*; D013844:Thiazoles / Q000032:analysis; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D005290:Ferric Compounds; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T; D012967:Sodium Dodecyl Sulfate; D004298:Dopamine