Reversible inhibition of α-synuclein fibrillization by dopaminochrome-mediated conformational alterations

被引:227
作者
Norris, EH
Giasson, BI
Hodara, R
Xu, SH
Trojanowski, JQ
Ischiropoulos, H
Lee, VMY [1 ]
机构
[1] Univ Penn, Inst Aging, Ctr Neurodegenerat Dis Res, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
[2] Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 USA
[3] Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA
[4] Childrens Hosp Philadelphia, Stokes Res Inst, Philadelphia, PA 19104 USA
关键词
D O I
10.1074/jbc.M412621200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Previous studies demonstrated that alpha-synuclein (alpha-syn) fibrillization is inhibited by dopamine, and studies to understand the molecular basis of this process were conducted (Conway, K. A., Rochet, J. C., Bieganski, R. M., and Lansbury, P. T., Jr. ( 2001) Science 294, 1346-1349). Dopamine inhibition of alpha-syn fibrillization generated exclusively spherical oligomers that depended on dopamine autoxidation but not alpha-syn oxidation, because mutagenesis of Met, His, and Tyr residues in alpha-syn did not abrogate this inhibition. However, truncation of alpha-syn at residue 125 restored the ability of alpha-syn to fibrillize in the presence of dopamine. Mutagenesis and competition studies with specific synthetic peptides identified alpha-syn residues 125-129 (i.e. YEMPS) as an important region in the dopamine-induced inhibition of alpha-syn fibrillization. Significantly, the dopamine oxidation product dopaminochrome was identified as a specific inhibitor of alpha-syn fibrillization. Dopaminochrome promotes the formation of spherical oligomers by inducing conformational changes, as these oligomers regained the ability to fibrillize by simple denaturation/ renaturation. Taken together, these data indicate that dopamine inhibits alpha-syn fibrillization by inducing structural changes in alpha-syn that can occur through the interaction of dopaminochrome with the (YEMPS129)-Y-125 motif of alpha-syn. These results suggest that the dopamine autoxidation can prevent alpha-syn fibrillization in dopaminergic neurons through a novel mechanism. Thus, decreased dopamine levels in substantia nigra neurons might promote alpha-syn aggregation in Parkinson's disease.
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收藏
页码:21212 / 21219
页数:8
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