Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: Implications for lewy body formation

Leong Lim Kah, Katherine C.M. Chew, Jeanne M.M. Tan, Cheng Wang, Kenny K.K. Chung, Yi Zhang, Yuji Tanaka, Wanli Smith, Simone Engelender, Christopher A. Ross, Valina L. Dawson, Ted M. Dawson

Research output: Contribution to journalArticle

Abstract

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, α-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.

Original languageEnglish (US)
Pages (from-to)2002-2009
Number of pages8
JournalJournal of Neuroscience
Volume25
Issue number8
DOIs
StatePublished - Feb 23 2005

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Keywords

  • Dopamine
  • Lewy body
  • Parkin
  • Parkinson's disease
  • Synphilin-1
  • Ubiquitin

ASJC Scopus subject areas

  • Neuroscience(all)

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