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J. Biol. Chem., Vol. 280, Issue 26, 25216-25224, July 1, 2005

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Proteolytic Cleavage of Extracellular Secreted -Synuclein via Matrix Metalloproteinases^*

Jee Young Sung, Sung Min Park, Choong-Hwan Lee¶, Ji Won Um||, Hyun Jung Lee||, Jongsun Kim**, Young J. Oh||, Seung-Taek Lee, Seung R. Paik¶, and Kwang Chul Chung||

From the ^||Department of Biology, the Department of Biochemistry, College of Science, Yonsei University, Seoul 120-749, Korea, the ^**Department of Microbiology, College of Medicine, Yonsei University, Seoul 120-752, Korea, the ^¶School of Chemical and Biological Engineering, College of Engineering, Seoul National University, Seoul 151-744, Korea, and the Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021

Although -synuclein is the main structural component of the insoluble filaments that form Lewy bodies in Parkinson disease (PD), its physiological function and exact role in neuronal death remain poorly understood. In the present study, we examined the possible functional relationship between -synuclein and several forms of matrix metalloproteinases (MMPs) in the human dopaminergic neuroblastoma (SK-N-BE) cell line. When SK-N-BE cells were transiently transfected with -synuclein, it was secreted into the extracellular culture media, concomitantly with a significant decrease in cell viability. Also the addition of nitric oxide-generating compounds to the cells caused the secreted -synuclein to be digested, producing a small fragment whose size was similar to that of the fragment generated during the incubation of -synuclein with various MMPs in vitro. Among several forms of MMPs, -synuclein was cleaved most efficiently by MMP-3, and MALDI-TOF mass spectra analysis showed that -synuclein is cleaved from its C-terminal end with at least four cleavage sites within the non-A component of AD amyloid sequence. Compared with the intact form, the protein aggregation of -synuclein was remarkably facilitated in the presence of the proteolytic fragments, and the fragment-induced aggregates showed more toxic effect on cell viability. Moreover, the levels of MMP-3 were also found to be increased significantly in the rat PD brain model produced by the cerebral injection of 6-hydroxydopamine into the substantia nigra. The present study suggests that the extracellularly secreted -synuclein could be processed via the activation of MMP-3 in a selective manner.

Received for publication, March 28, 2005 , and in revised form, April 26, 2005.

^* This work was supported by the Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology (MOST) of the Republic of Korea (Grant M103KV010006-03K2201-00640 (to K. C. C.), by the Korea Health 21 R&D Project, Ministry of Health & Welfare (Grant 03-PJ1-PG10-21300-0023 to K. C. C.), by a Basic Research Grant of Korea Science and Engineering Foundation (Grant R01-2004-000-10673-0 to K. C. C.), by Molecular and Cellular BioDiscovery Research Program Grant from MOST (Grant M1-0311-00-0028 to S. R. P.), and by the National Research Laboratory program of MOST (Grant 2000-N-NL-01-C-244 to S.-T. 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.

To whom correspondence may be addressed: Tel.: 82-2-880-7402; Fax: 82-2-888-1604; E-mail:srpaik{at}snu.ac.kr.

To whom correspondence may be addressed: Tel.: 82-2-2123-2653; Fax: 82-2-312-5657; E-mail: kchung{at}yonsei.ac.kr.

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