Dopamine and the dopamine oxidation product 5,6-dihydroxylindole promote distinct on-pathway and off-pathway aggregation of alpha-synuclein in a pH-dependent manner.
The deposition of alpha-synuclein (alpha-syn) aggregates in dopaminergic neurons is a key feature of Parkinson's disease. While dopamine (DA) can modulate alpha-syn aggregation, it is unclear which other factors can regulate the actions of DA on alpha-syn. In this study, we investigated the effect of solution conditions (buffer, salt and pH) on the oligomerization of alpha-syn by DA. We show that alpha-syn oligomerization is dependent on the oxidation of DA into reactive intermediates. Under acidic pH conditions, DA is stable, and DA-mediated oligomerization of alpha-syn is inhibited. From pH 7.0 to pH 11.0, DA is unstable and undergoes redox reactions, promoting the formation of SDS-resistant soluble oligomers of alpha-syn. We show that the reactive intermediate 5,6-dihydroxylindole mediates the formation of alpha-syn soluble oligomers under physiological conditions (pH 7.4). In contrast, under acidic conditions (pH 4.0), 5,6-dihydroxylindole promotes the formation of SDS-resistant insoluble oligomers that further associate to form sheet-like fibrils with beta-sheet structure that do not bind the dye thioflavin T. These results suggest that distinct reactive intermediates of DA, and not DA itself, interact with alpha-syn to generate the alpha-syn aggregates implicated in Parkinson's disease.
Department of Pathology, The University of Melbourne, Victoria, Australia.
Chi L L
CL
Pham
Su Ling
SL
Leong
Feda E
FE
Ali
Vijaya B
VB
Kenche
Andrew F
AF
Hill
Sally L
SL
Gras
Kevin J
KJ
Barnham
Roberto
R
Cappai
D000975:Antioxidants / Q000737:chemistry; D002021:Buffers; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000378:metabolism; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012492:Salts / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure
D000975:Antioxidants; D002021:Buffers; D007211:Indoles; D012492:Salts; D051844:alpha-Synuclein; D004298:Dopamine; C033871:5,6-dihydroxyindole