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J. Biol. Chem., Vol. 282, Issue 43, 31621-31630, October 26, 2007

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Cellular Oligomerization of -Synuclein Is Determined by the Interaction of Oxidized Catechols with a C-terminal Sequence^*

Joseph R. Mazzulli, Maria Armakola, Michelle Dumoulin, Ioannis Parastatidis, and Harry Ischiropoulos¹

From the Joseph Stokes Jr. Research Institute and Department of Pediatrics and Pharmacology, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania 19104

The mechanisms that govern the formation of -synuclein (-syn) aggregates are not well understood but are considered a central event in the pathogenesis of Parkinson's disease (PD). A critically important modulator of -syn aggregation in vitro is dopamine and other catechols, which can prevent the formation of -syn aggregates in cell-free and cellular model systems. Despite the profound importance of this interaction for the pathogenesis of PD, the processes by which catechols alter -syn aggregation are unclear. Molecular and biochemical approaches were employed to evaluate the mechanism of catechol--syn interactions and the effect on inclusion formation. The data show that the intracellular inhibition of -syn aggregation requires the oxidation of catechols and the specific noncovalent interaction of the oxidized catechols with residues ¹²⁵YEMPS¹²⁹ in the C-terminal region of the protein. Cell-free studies using novel near infrared fluorescence methodology for the detection of covalent protein-ortho-quinone adducts showed that although covalent modification of -syn occurs, this does not affect -syn fibril formation. In addition, oxidized catechols are unable to prevent both thermal and acid-induced protein aggregation as well as fibrils formed from a protein that lacks a YEMPS amino acid sequence, suggesting a specific effect for -syn. These results suggest that inappropriate C-terminal cleavage of -syn, which is known to occur in vivo in PD brain or a decline of intracellular catechol levels might affect disease progression, resulting in accelerated -syn inclusion formation and dopaminergic neurodegeneration.

Received for publication, June 8, 2007 , and in revised form, August 31, 2007.

^* This work was supported by United States Public Health Service Grants AG13966 and ES013508 from the NIEHS, National Institutes of Health, Center of Excellence in Environmental Toxicology. 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 Figs. S1-S4.

¹ To whom correspondence should be addressed: Stokes Research Institute, Children's Hospital of Philadelphia, 416D Abramson Research Center, 3517 Civic Center Blvd., Philadelphia, PA 19104-4318. Tel.: 215-590-5320; Fax: 215-590-4267; E-mail: ischirop{at}mail.med.upenn.edu.

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