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 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

Fingerprint

Lewy Bodies
Ubiquitination
Ubiquitin
Ligases
Lysine
Parkinson Disease
Synucleins
Polyubiquitin
Proteasome Endopeptidase Complex
Proteins
Genes

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1 : Implications for lewy body formation. / Kah, Leong Lim; Chew, Katherine C M; Tan, Jeanne M M; Wang, Cheng; Chung, Kenny K K; Zhang, Yi; Tanaka, Yuji; Smith, Wanli; Engelender, Simone; Ross, Christopher A; Dawson, Valina; Dawson, Ted M.

In: Journal of Neuroscience, Vol. 25, No. 8, 23.02.2005, p. 2002-2009.

Research output: Contribution to journalArticle

Kah, Leong Lim ; Chew, Katherine C M ; Tan, Jeanne M M ; Wang, Cheng ; Chung, Kenny K K ; Zhang, Yi ; Tanaka, Yuji ; Smith, Wanli ; Engelender, Simone ; Ross, Christopher A ; Dawson, Valina ; Dawson, Ted M. / Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1 : Implications for lewy body formation. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 8. pp. 2002-2009.
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