title: Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: implications for Lewy body formation.
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, alpha-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.
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Kah Leong
authors.initials: KL
authors.lastname: Lim
authors.forename: Katherine C M
authors.initials: KC
authors.lastname: Chew
authors.forename: Jeanne M M
authors.initials: JM
authors.lastname: Tan
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Kenny K K
authors.initials: KK
authors.lastname: Chung
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Wanli
authors.initials: W
authors.lastname: Smith
authors.forename: Simone
authors.initials: S
authors.lastname: Engelender
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002384:Catalysis; D002460:Cell Line; D015870:Gene Expression; D006801:Humans; D007668:Kidney; D016631:Lewy Bodies / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D051843:Synucleins; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051844:alpha-Synuclein
chemical_list: D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C497604:SNCA protein, human; C118958:SNCAIP protein, human; D051843:Synucleins; D025801:Ubiquitin; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex; D008239:Lysine
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