Ubiquitylation of synphilin-1 and α-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease

Esti Liani, Allon Eyal, Eyal Avraham, Revital Shemer, Raymonde Szargel, Daniela Berg, Antje Bornemann, Olaf Riess, Christopher A. Ross, Ruth Rott, Simone Engelender

Research output: Contribution to journalArticlepeer-review

Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by Lewy body formation and death of dopaminergic neurons. Mutations in α-synuclein and parkin cause familial forms of PD. Synphilin-1 was shown to interact with α-synuclein and to promote the formation of cytosolic inclusions. We now report that synphilin-1 interacts with the E3 ubiquitin-ligases SIAH-1 and SIAH-2. SIAH proteins ubiquitylate synphilin-1 both in vitro and in vivo, promoting its degradation by the ubiquitin-proteasome system. Inability of the proteasome to degrade synphilin-1/SIAH complex leads to a robust formation of ubiquitylated cytosolic inclusions. Ubiquitylation is required for inclusion formation, because a catalytically inactive mutant of SIAH-1, which still binds to synphilin-1, fails to promote inclusions. Like synphilin-1, α-synuclein associates with SIAH in intact cells, but the interaction with SIAH-2 was much stronger that with SIAH-1. In vitro experiments show that SIAH-2 monoubiquitylates α-synuclein. Further evidence that SIAH proteins may play a role in inclusion formation comes from the demonstration of SIAH immunoreactivity in Lewy bodies of PD patients.

Original languageEnglish (US)
Pages (from-to)5500-5505
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number15
DOIs
StatePublished - Apr 13 2004

Keywords

  • Inclusion bodies
  • Ubiquitin
  • α-synuclein-interacting protein

ASJC Scopus subject areas

  • General

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