title: Guanidine hydrochloride denaturation of dopamine-induced α-synuclein oligomers: a small-angle X-ray scattering study.
abstract: Alpha-synuclein (α-syn) forms the amyloid-containing Lewy bodies found in the brain in Parkinson's disease. The neurotransmitter dopamine (DA) reacts with α-syn to form SDS-resistant soluble, non-amyloid, and melanin-containing oligomers. Their toxicity is debated, as is the nature of their structure and their relation to amyloid-forming conformers of α-syn. The small-angle X-ray scattering technique in combination with modeling by the ensemble optimization method showed that the un-reacted native protein populated three broad classes of conformer, while reaction with DA gave a restricted ensemble range suggesting that the rigid melanin molecule played an important part in their structure. We found that 6 M guanidine hydrochloride did not dissociate α-syn DA-reacted dimers and trimers, suggesting covalent linkages. The pathological significance of covalent association is that if they are non-toxic, the oligomers would act as a sink for toxic excess DA and α-syn; if toxic, their stability could enhance their toxicity. We argue it is essential, therefore, to resolve the question of whether they are toxic or not.
authors.affiliation: Department of Pathology and Bio21 Molecular Science and Technology Institute, The University of Melbourne, Victoria, 3010, Australia.
authors.forename: Chi L L
authors.initials: CL
authors.lastname: Pham
authors.forename: Nigel
authors.initials: N
authors.lastname: Kirby
authors.forename: Kathleen
authors.initials: K
authors.lastname: Wood
authors.forename: Timothy
authors.initials: T
authors.lastname: Ryan
authors.forename: Blaine
authors.initials: B
authors.lastname: Roberts
authors.forename: Anna
authors.initials: A
authors.lastname: Sokolova
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Robert B
authors.initials: RB
authors.lastname: Knott
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
authors.forename: Cyril C
authors.initials: CC
authors.lastname: Curtain
authors.forename: Agata
authors.initials: A
authors.lastname: Rekas
mesh_terms: D001921:Brain / Q000378:metabolism*; D016000:Cluster Analysis; D004298:Dopamine / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli; D019791:Guanidine / Q000378:metabolism*; D006801:Humans; D008956:Models, Chemical; D010300:Parkinson Disease / Q000378:metabolism*; D011489:Protein Denaturation; D012542:Scattering, Radiation; D014461:Ultracentrifugation; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D019791:Guanidine; D004298:Dopamine
keywords: Parkinson's disease; dopamine; oligomers; small-angle X-ray scattering; α-synuclein