Title of article :
Dopamine and the Dopamine Oxidation Product 5,6-Dihydroxylindole Promote Distinct On-Pathway and Off-Pathway Aggregation of α-Synuclein in a pH-Dependent Manner
Author/Authors :
Chi L.L. Pham، نويسنده , , Su Ling Leong، نويسنده , , Feda E. Ali، نويسنده , , Vijaya B. Kenche، نويسنده , , Andrew F. Hill، نويسنده , , Sally L. Gras، نويسنده , , Kevin J. Barnham، نويسنده , , Roberto Cappai، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2009
Abstract :
The deposition of α-synuclein (α-syn) aggregates in dopaminergic neurons is a key feature of Parkinsonʹs disease. While dopamine (DA) can modulate α-syn aggregation, it is unclear which other factors can regulate the actions of DA on α-syn. In this study, we investigated the effect of solution conditions (buffer, salt and pH) on the oligomerization of α-syn by DA. We show that α-syn oligomerization is dependent on the oxidation of DA into reactive intermediates. Under acidic pH conditions, DA is stable, and DA-mediated oligomerization of α-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 α-syn. We show that the reactive intermediate 5,6-dihydroxylindole mediates the formation of α-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 β-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 α-syn to generate the α-syn aggregates implicated in Parkinsonʹs disease.
Keywords :
Dopamine , ?-synuclein , Parkinsonיs disease , amyloid , Oligomer
Journal title :
Journal of Molecular Biology
Journal title :
Journal of Molecular Biology