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J. Biol. Chem., Vol. 279, Issue 8, 6834-6839, February 20, 2004

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Casein Kinase II-mediated Phosphorylation Regulates -Synuclein/Synphilin-1 Interaction and Inclusion Body Formation^*

Gwang Lee, Mikiei Tanaka, Kiho Park¶, Sang Seop Lee||, Yong Man Kim**, Eunsung Junn, Sang-Hyeon Lee, and M. Maral Mouradian¶¶

From the Genetic Pharmacology Unit, NINDS, National Institutes of Health, Bethesda, Maryland 20824, Department of Neurology, University of Medicine and Dentistry-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and Laboratory of Medical Genetics, Ajou University School of Medicine, Ajou University, Wonchon-Dong, Paldal-Gu, Suwon 442-721, Korea

-Synuclein is a phosphoprotein that accumulates as a major component of Lewy bodies in the brains of patients with Parkinson disease. Synphilin-1, which is also present in Lewy bodies, binds with -synuclein and forms cytoplasmic inclusions in transfected cells. Yet the molecular determinants of this protein-protein interaction are unknown. Here we report that casein kinase II (CKII) phosphorylates synphilin-1 and that the subunit of this enzyme complex binds to synphilin-1. Additionally, both CKII and subunits are present within cytoplasmic inclusions in cells that overexpress synphilin-1. Notably, the interaction between synphilin-1 and -synuclein is markedly dependent on phosphorylation. Inhibition of CKII activity by 5,6-dichloro-1--D-ribofuranosylbenzimidazole blocks the binding between these two proteins and significantly reduces the percentage of cells that contain eosinophilic cytoplasmic inclusions. Mutation of the major CKII phosphorylation site in -synuclein (S129A) has no significant impact on the binding between -synuclein and synphilin-1 or on the formation of synphilin-1/-synuclein-positive inclusions. These data suggest that the CKII-mediated phosphorylation of synphilin-1 rather than that of -synuclein is critical in modulating their tendency to aggregate into inclusions. These observations collectively indicate that a ubiquitous post-translational modification such as phosphorylation can regulate inclusion body formation in the context of -synuclein and synphilin-1 interaction.

Received for publication, November 21, 2003

^* This work was supported in part by Korea Research Foundation Grant KRF-2001-005-F20002 (to G. L.). 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.

^¶ Present address: Dept. of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea.

^|| Present address: Dept. of Pharmacology, Inje University College of Medicine, 633-165, Kaekum-dong, Jin-ku, Busan 614-735, Korea.

^** Present address: Dept. of Parasitology, College of Medicine, Wonkwang University, Jeonbuk, Korea.

Present address: Dept. of Bioscience and Biotechnology, Silla University, Kwaebop-dong, Sasang-gu, Busan 617-736, Korea.

^¶¶ To whom correspondence should be addressed: William Dow Lovett Professor of Neurology, Department of Neurology, UMDNJ/Robert Wood Johnson Medical School, 683 Hoes Lane, Rm. 180, Piscataway, NJ 08854. Tel.: 732-235-4772; Fax: 732-235-4773; E-mail: mouradian{at}umdnj.edu.

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