Parkin ubiquitinates the α-synuclein-interacting protein, synphilin-1: Implications for Lewy-body formation in Parkinson disease

Kenny K.K. Chung, Yi Zhang, Kah Leong Lim, Yuji Tanaka, Hui Huang, Jun Gao, Christopher A. Ross, Valina L. Dawson, Ted M. Dawson

Research output: Contribution to journalArticlepeer-review

Abstract

Parkinson disease is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and the presence of intracytoplasmic-ubiquitinated inclusions (Lewy bodies). Mutations in α-synuclein (A53T, A30P) and parkin cause familial Parkinson disease. Both these proteins are found in Lewy bodies. The absence of Lewy bodies in patients with parkin mutations suggests that parkin might be required for the formation of Lewy bodies. Here we show that parkin interacts with and ubiquitinates the α-synuclein-interacting protein, synphilin-1. Co-expression of α-synuclein, synphilin-1 and parkin result in the formation of Lewy-body-like ubiquitin-positive cytosolic inclusions. We further show that familial-linked mutations in parkin disrupt the ubiquitination of synphilin-1 and the formation of the ubiquitin-positive inclusions. These results provide a molecular basis for the ubiquitination of Lewy-body-associated proteins and link parkin and α-synuclein in a common pathogenic mechanism through their interaction with synphilin-1.

Original languageEnglish (US)
Pages (from-to)1144-1150
Number of pages7
JournalNature medicine
Volume7
Issue number10
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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