title: Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease.
abstract: Parkinson's disease (PD) is a neurodegenerative disease characterized by Lewy body formation and death of dopaminergic neurons. Mutations in alpha-synuclein and parkin cause familial forms of PD. Synphilin-1 was shown to interact with alpha-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, alpha-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 alpha-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.
authors.affiliation: Department of Pharmacology, The B. Rappaport Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Esti
authors.initials: E
authors.lastname: Liani
authors.forename: Allon
authors.initials: A
authors.lastname: Eyal
authors.forename: Eyal
authors.initials: E
authors.lastname: Avraham
authors.forename: Revital
authors.initials: R
authors.lastname: Shemer
authors.forename: Raymonde
authors.initials: R
authors.lastname: Szargel
authors.forename: Daniela
authors.initials: D
authors.lastname: Berg
authors.forename: Antje
authors.initials: A
authors.lastname: Bornemann
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: Ruth
authors.initials: R
authors.lastname: Rott
authors.forename: Simone
authors.initials: S
authors.lastname: Engelender
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D016631:Lewy Bodies / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D051843:Synucleins; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein; D000098563:Seven in Absentia Proteins
chemical_list: D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; C497604:SNCA protein, human; C118958:SNCAIP protein, human; C497606:Snca protein, rat; C498463:Sncaip protein, rat; D051843:Synucleins; D014157:Transcription Factors; D025801:Ubiquitin; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins