当前位置： SCI文献检索 > JOURNAL OF MOLECULAR BIOLOGY期刊下所有文献 > 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.

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.

Abstract：

: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.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Pham CL,Leong SL,Ali FE,Kenche VB,Hill AF,Gras SL,Barnham KJ,Cappai R

doi

10.1016/j.jmb.2009.02.007

subject

Has Abstract

pub_date

2009-04-03 00:00:00

pages

771-85

issue

3

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(09)00149-1

journal_volume

387

pub_type

杂志文章

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