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J. Biol. Chem., Vol. 281, Issue 40, 29739-29752, October 6, 2006

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Phosphorylation of Ser-129 Is the Dominant Pathological Modification of -Synuclein in Familial and Sporadic Lewy Body Disease^*

John P. Anderson, Donald E. Walker, Jason M. Goldstein, Rian de Laat, Kelly Banducci, Russell J. Caccavello, Robin Barbour, Jiping Huang, Kristin Kling, Michael Lee, Linnea Diep, Pamela S. Keim, Xiaofeng Shen, Tim Chataway, Michael G. Schlossmacher^¶1, Peter Seubert, Dale Schenk, Sukanto Sinha, Wei Ping Gai², and Tamie J. Chilcote³

From the Elan Pharmaceuticals, South San Francisco, California 94080, the Flinders University School of Medicine, Bedford Park, SA5042, Australia, and the ^¶Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

A comprehensive, unbiased inventory of synuclein forms present in Lewy bodies from patients with dementia with Lewy bodies was carried out using two-dimensional immunoblot analysis, novel sandwich enzyme-linked immunosorbent assays with modification-specific synuclein antibodies, and mass spectroscopy. The predominant modification of -synuclein in Lewy bodies is a single phosphorylation at Ser-129. In addition, there is a set of characteristic modifications that are present to a lesser extent, including ubiquitination at Lys residues 12, 21, and 23 and specific truncations at Asp-115, Asp-119, Asn-122, Tyr-133, and Asp-135. No other modifications are detectable by tandem mass spectrometry mapping, except for a ubiquitous N-terminal acetylation. Small amounts of Ser-129 phosphorylated and Asp-119-truncated -synuclein are present in the soluble fraction of both normal and disease brains, suggesting that these Lewy body-associated forms are produced during normal metabolism of -synuclein. In contrast, ubiquitination is only detected in Lewy bodies and is primarily present on phosphorylated synuclein; it therefore likely occurs after phosphorylated synuclein has deposited into Lewy bodies. This invariant pattern of specific phosphorylation, truncation, and ubiquitination is also present in the detergent-insoluble fraction of brain from patients with familial Parkinson's disease (synuclein A53T mutation) as well as multiple system atrophy, suggesting a common pathogenic pathway for both genetic and sporadic Lewy body diseases. These observations are most consistent with a model in which preferential accumulation of normally produced Ser-129 phosphorylated -synuclein is the key event responsible for the formation of Lewy bodies in various Lewy body diseases.

Received for publication, January 31, 2006 , and in revised form, June 26, 2006.

^* 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 Figs. S1–S6 and Tables S1 and S2.

¹ Supported by NINDS/National Institutes of Health.

² Funded by the National Health and Medical Research Council of Australia, the Michael J. Fox Foundation, and Elan Pharmaceuticals.

³ To whom correspondence should be addressed: ActiveSite Pharmaceuticals, 187 Magellan Ave., San Francisco, CA 94116. Tel.: 415-596-7660; Fax: 415-276-8935; E-mail: tamie.chilcote{at}activesitepharma.com.

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