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J. Biol. Chem., Vol. 278, Issue 31, 29106-29114, August 1, 2003

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Dorfin Localizes to Lewy Bodies and Ubiquitylates Synphilin-1^*

Takashi Ito, Jun-ichi Niwa , Nozomi Hishikawa, Shinsuke Ishigaki, Manabu Doyu and Gen Sobue 

From the Department of Neurology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan

Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of nigra dopaminergic neurons. Lewy bodies (LBs) are a characteristic neuronal inclusion in PD brains. In this study, we report that Dorfin, a RING finger-type ubiquityl ligase for mutant superoxide dismutase-1, was localized with ubiquitin in LBs. Recently, synphilin-1 was identified to associate with -synuclein and to be a major component of LBs. We found that overexpression of synphilin-1 in cultured cells led to the formation of large juxtanuclear inclusions, but showed no cytotoxicity. Dorfin colocalized in these large inclusions with ubiquitin and proteasomal components. In contrast to full-length synphilin-1, overexpression of the central portion of synphilin-1, including ankyrin-like repeats, a coiled-coil domain, and an ATP/GTP-binding domain, predominantly led to the formation of small punctate aggregates scattered throughout the cytoplasm and showed cytotoxic effects. Dorfin and ubiquitin did not localize in these small aggregates. Overexpression of the N or C terminus of synphilin-1 did not lead to the formation of any aggregates. Dorfin physically bound and ubiquitylated synphilin-1 through its central portion, but did not ubiquitylate wild-type or mutant -synuclein. These results suggest that the central domain of synphilin-1 has an important role in the formation of aggregates and cytotoxicity and that Dorfin may be involved in the pathogenic process of PD and LB formation by ubiquitylation of synphilin-1.

Received for publication, March 18, 2003 , and in revised form, May 12, 2003.

^* This work was supported in part by a Center of Excellence grant from the Ministry of Education, Culture, Sports, Science, and Technology and by grants from the Ministry of Health, Labor, and Welfare of Japan. 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.

Research Fellow of the Japan Society for the Promotion of Science for Young Scientists.

To whom correspondence should be addressed: Dept. of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Tel.: 81-52-744-2385; Fax: 81-52-744-2384; E-mail: sobueg{at}med.nagoya-u.ac.jp.

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