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J. Biol. Chem., Vol. 282, Issue 19, 14558-14566, May 11, 2007

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Assembly of Lysine 63-linked Ubiquitin Conjugates by Phosphorylated -Synuclein Implies Lewy Body Biogenesis^*

Chao Liu, Erkang Fei, Nali Jia, Hongfeng Wang, Ruisong Tao, Atsushi Iwata, Nobuyuki Nukina, Jiangning Zhou, and Guanghui Wang¹

From the Hefei National Laboratory for Physical Sciences at Microscale and Department of Neurobiology, School of Life Sciences, University of Science & Technology of China, Hefei, Anhui 230027, China and the Laboratory for Structure Neuropathology, RIKEN Brain Science Institute, Saitama 351-0198, Japan

-Synuclein (-syn) and ubiquitin (Ub) are major protein components deposited in Lewy bodies (LBs) and Lewy neurites, which are pathologic hallmarks of idiopathic Parkinson disease (PD). Almost 90% of -syn in LBs is phosphorylated at serine 129 (Ser¹²⁹). However, the role of Ser¹²⁹-phosphorylated -syn in the biogenesis of LBs remains unclear. Here, we show that compared with coexpression of wild type (WT)-syn and Ub, coexpression of phospho-mimic mutant -syn (S129D) and Ub in neuro2a cells results in an increase of Ub-conjugates and the formation of ubiquitinated inclusions. Furthermore, S129D -syn fails to increase the Ub-conjugates and form ubiquitinated inclusions in the presence of a K63R mutant Ub. In addition, as compared with WT -syn, S129D -syn increased cytoplasmic and neuritic aggregates of itself in neuro2a cells treated with H₂O₂ and serum deprivation. These results suggest that the contribution of Ser¹²⁹-phosphorylated -syn to the Lys⁶³-linked Ub-conjugates and aggregation of itself may be involved in the biogenesis of LBs in Parkinson disease and other related synucleinopathies.

Received for publication, January 16, 2007 , and in revised form, March 7, 2007.

^* This work was supported by National Natural Sciences Foundation of China Grant 30470538, National High-tech Research and Development program of China 973-project 2006CB500703 and 863-project 2006AA02Z184, the Collaboration Foundation (2004) from the RIKEN Brain Science Institute, Japan, and the 111 Project of China. 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. S1.

¹ To whom correspondence should be addressed. Tel.: 86-551-3607058; Fax: 86-551-3607058; E-mail: wghui{at}ustc.edu.cn.

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