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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2004-04, Vol.101 (15), p.5500-5505
• Main Authors: Liani, Esti, Eyal, Allon, Avraham, Eyal, Shemer, Revital, Szargel, Raymonde, Berg, Daniela, Bornemann, Antje, Riess, Olaf, Ross, Christopher A., Rott, Ruth, Engelender, Simone, Hershko, Avram
• Format: Article
• Language: English
• Subjects: alpha-Synuclein; Amino acids; Animals; Antibodies; Biochemistry; Biological Sciences; Brain - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Drug interactions; Humans; Inclusion bodies; Inclusion Bodies - metabolism; Lewy bodies; Lewy Bodies - metabolism; Lewy body disease; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Parkinson disease; Parkinson Disease - metabolism; Parkinson's disease; Protein Binding; Proteins; Proteins - metabolism; Rats; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Substantia nigra; Synucleins; Transcription Factors - metabolism; Transfection; Ubiquitin - metabolism; Ubiquitin-Protein Ligases; Ubiquitins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0401081101

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.