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The Journal of Neuroscience, February 23, 2005, 25(8):2002-2009; doi:10.1523/JNEUROSCI.4474-04.2005

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Neurobiology of Disease
Parkin Mediates Nonclassical, Proteasomal-Independent Ubiquitination of Synphilin-1: Implications for Lewy Body Formation

Kah Leong Lim,^1,2,6,7 Katherine C. M. Chew,^6,7 Jeanne M. M. Tan,⁶ Cheng Wang,^6,7 Kenny K. K. Chung,^1,2 Yi Zhang,^1,3 Yuji Tanaka,⁴ Wanli Smith,⁴ Simone Engelender,⁸ Christopher A. Ross,^2,3,4 Valina L. Dawson,^1,2,3,5 and Ted M. Dawson^1,2,3

¹Institute for Cell Engineering, Departments of ²Neurology and ³Neuroscience, ⁴Division of Neurobiology, ⁵Department of Psychiatry and Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, ⁶Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore, S308433, ⁷Department of Biological Sciences, National University of Singapore, Singapore, S117542, and ⁸Department of Pharmacology, Technion-Israel Institute of Technology, Haifa 31096, Israel

It is widely accepted that the familial Parkinson's disease (PD)-linked gene product, parkin, functions as a ubiquitin ligase involved in protein turnover via the ubiquitin-proteasome system. Substrates ubiquitinated by parkin are hence thought to be destined for proteasomal degradation. Because we demonstrated previously that parkin interacts with and ubiquitinates synphilin-1, we initially expected synphilin-1 degradation to be enhanced in the presence of parkin. Contrary to our expectation, we found that synphilin-1 is normally ubiquitinated by parkin in a nonclassical, proteasomal-independent manner that involves lysine 63 (K63)-linked polyubiquitin chain formation. Parkin-mediated degradation of synphilin-1 occurs appreciably only at an unusually high parkin to synphilin-1 expression ratio or when primed for lysine 48 (K48)-linked ubiquitination. In addition we found that parkin-mediated ubiquitination of proteins within Lewy-body-like inclusions formed by the coexpression of synphilin-1, -synuclein, and parkin occurs predominantly via K63 linkages and that the formation of these inclusions is enhanced by K63-linked ubiquitination. Our results suggest that parkin is a dual-function ubiquitin ligase and that K63-linked ubiquitination of synphilin-1 by parkin may be involved in the formation of Lewy body inclusions associated with PD.

Key words: parkin; synphilin-1; ubiquitin; Parkinson's disease; Lewy body; dopamine

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Received Oct 31, 2004; revised January 6, 2005; accepted January 6, 2005.

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