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
| Autor: | Olaf Riess, Simone Engelender, Daniela Berg, Antje Bornemann, Esti Liani, Raymonde Szargel, Revital Shemer, Christopher A. Ross, Allon Eyal, Ruth Rott, Eyal Avraham |
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| Rok vydání: | 2004 |
| Předmět: |
Parkinson's disease
Recombinant Fusion Proteins Ubiquitin-Protein Ligases Mutant Synucleins Nerve Tissue Proteins Biology Transfection Parkin Cell Line Ubiquitin medicine Animals Humans Inclusion Bodies Multidisciplinary Lewy body Synphilin-1 Brain Nuclear Proteins Proteins Parkinson Disease Biological Sciences medicine.disease Molecular biology Rats Cell biology Cytosol Proteasome alpha-Synuclein biology.protein Lewy Bodies Carrier Proteins Protein Binding Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences. 101:5500-5505 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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