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J. Biol. Chem., Vol. 280, Issue 22, 21212-21219, June 3, 2005

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Reversible Inhibition of -Synuclein Fibrillization by Dopaminochrome-mediated Conformational Alterations^*

Erin H. Norris, Benoit I. Giasson¶, Roberto Hodara||**, Shaohua Xu, John Q. Trojanowski, Harry Ischiropoulos||**, and Virginia M.-Y. Lee

From the Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging and the Departments of ^¶Pharmacology and ^||Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and the ^**Stokes Research Institute, Children's Hospital of Philadelphia, Philadelphia Pennsylvania 19104

Previous studies demonstrated that -synuclein (-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 -syn fibrillization generated exclusively spherical oligomers that depended on dopamine autoxidation but not -syn oxidation, because mutagenesis of Met, His, and Tyr residues in -syn did not abrogate this inhibition. However, truncation of -syn at residue 125 restored the ability of -syn to fibrillize in the presence of dopamine. Mutagenesis and competition studies with specific synthetic peptides identified -syn residues 125–129 (i.e. YEMPS) as an important region in the dopamine-induced inhibition of -syn fibrillization. Significantly, the dopamine oxidation product dopaminochrome was identified as a specific inhibitor of -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 -syn fibrillization by inducing structural changes in -syn that can occur through the interaction of dopaminochrome with the ¹²⁵YEMPS¹²⁹ motif of -syn. These results suggest that the dopamine autoxidation can prevent -syn fibrillization in dopaminergic neurons through a novel mechanism. Thus, decreased dopamine levels in substantia nigra neurons might promote -syn aggregation in Parkinson's disease.

Received for publication, November 8, 2004 , and in revised form, March 23, 2005.

^* This work was supported by National Institutes of Health Grants AG09215 and NS044233 and by the Picower Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1 concerning the inhibition of -syn polymerization by dopamine or dopaminochrome in samples incubated without oil overlay.

These two authors contributed equally to this paper.

The Measey-Schnabel Professor of Aging Research.

The John H. Ware III Professor of Alzheimer's Research and to whom correspondence should be addressed. Tel.: 215-662-6427; E-mail: vmylee{at}mail.med.upenn.edu.

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