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Please use this identifier to cite or link to this item: http://apo.ansto.gov.au/dspace/handle/10238/7779

Title: Guanidine hydrochloride denaturation of dopamine-induced α-synuclein oligomers: A small-angle X-ray scattering study
Authors: Pham, CLL
Kirby, N
Wood, K
Ryan, T
Roberts, B
Sokolova, A
Barnham, KJ
Masters, CL
Knott, RB
Cappai, R
Curtin, CC
Keywords: X-RAY DIFFRACTION
MELANIN
HYDROCHLORIC ACID
PATHOLOGY
COVALENCE
TOXINS
Issue Date: 31-Aug-2013
Publisher: Wiley Online Library
Citation: Pham, C. L. L., Kirby, N., Wood, K., Ryan, T., Roberts, B., Sokolova, A., . . . Rekas, A. (2014). Guanidine hydrochloride denaturation of dopamine-induced alpha-synuclein oligomers: A small-angle X-ray scattering study. Proteins-Structure Function and Bioinformatics, 82(1), 10-21. doi: http://dx.doi.org/10.1002/prot.24332
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. © 2013,Wiley Periodicals, Inc.
URI: http://dx.doi.org/10.1002/prot.24332
http://apo.ansto.gov.au/dspace/handle/10238/7779
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