ArticleThe Journal of biological chemistry2009
Synphilin-1A inhibits seven in absentia homolog (SIAH) and modulates alpha-synuclein monoubiquitylation and inclusion formation.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 34 citations in OpenAlex.
- The E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance.Cell death & disease · 2025Article
- Unique E2-binding specificity of artificial RING fingers in cancer cells.Scientific reports · 2024Article
- Antitumor Activity of Choerospondias axillaris Fruit Extract by Regulating the Expression of SNCAIP and SNCA on MDA-MB-231 Cells.Asian Pacific journal of cancer prevention : APJCP · 2022Article
- Atypical Ubiquitination and Parkinson's Disease.International journal of molecular sciences · 2022Review
- Deubiquitinating enzymes (DUBs): decipher underlying basis of neurodegenerative diseases.Molecular psychiatry · 2022Review
- Nicotine suppresses Parkinson's disease like phenotypes induced by Synphilin-1 overexpression in Drosophila melanogaster by increasing tyrosine hydroxylase and dopamine levels.Scientific reports · 2021Article
- SIAH2-mediated and organ-specific restriction of HO-1 expression by a dual mechanism.Scientific reports · 2020Article
- Nitric oxide contributes to protein homeostasis by S-nitrosylations of the chaperone HSPA8 and the ubiquitin ligase UBE2D.Redox biology · 2019Article
- Concise machinery for monitoring ubiquitination activities using novel artificial RING fingers.Protein science : a publication of the Protein Society · 2018Review
- MiR-30 Family Potentially Targeting PI3K-SIAH2 Predicted Interaction Network Represents a Novel Putative Theranostic Panel in Non-small Cell Lung Cancer.Frontiers in genetics · 2017Article
- Nuclear Compartmentalization of Serine Racemase Regulates D-Serine Production: IMPLICATIONS FOR N-METHYL-D-ASPARTATE (NMDA) RECEPTOR ACTIVATION.The Journal of biological chemistry · 2015Article
- The E3 ubiquitin ligase seven in absentia homolog 1 may be a potential new therapeutic target for Parkinson's disease.Neural regeneration research · 2015Article
- Regulators and effectors of Siah ubiquitin ligases.Cell biochemistry and biophysics · 2013Review
- Structure-based design of covalent Siah inhibitors.Chemistry & biology · 2013Article
- Bassoon and Piccolo maintain synapse integrity by regulating protein ubiquitination and degradation.The EMBO journal · 2013Article
- Article
- New brain-specific beta-synuclein isoforms show expression ratio changes in Lewy body diseases.Neurogenetics · 2012Article
- α-Synuclein fate is determined by USP9X-regulated monoubiquitination.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Interaction of an intracellular pentraxin with a BTB-Kelch protein is associated with ubiquitylation, aggregation and neuronal apoptosis.Molecular and cellular neurosciences · 2011Article
- Synphilin-1 inhibits alpha-synuclein degradation by the proteasome.Cellular and molecular life sciences : CMLS · 2011Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Parkinson disease (PD) is characterized by the presence of ubiquitylated inclusions and the death of dopaminergic neurons. Seven in absentia homolog (SIAH) is a ubiquitin-ligase that ubiquitylates alpha-synuclein and synphilin-1 and is present in Lewy bodies of PD patients. Understanding the mechanisms that regulate the ubiquitylation of PD-related proteins might shed light on the events involved in the formation of Lewy bodies and death of neurons. We show in this study that the recently described synphilin-1 isoform, synphilin-1A, interacts in vitro and in vivo with the ubiquitin-protein isopeptide ligase SIAH and regulates its activity toward alpha-synuclein and synphilin-1. SIAH promotes limited ubiquitylation of synphilin-1A that does not lead to its degradation by the proteasome. SIAH also increases the formation of synphilin-1A inclusions in the presence of proteasome inhibitors, supporting the participation of ubiquitylated synphilin-1A in the formation of Lewy body-like inclusions. Synphilin-1A/SIAH inclusions recruit PD-related proteins, such as alpha-synuclein, synphilin-1, Parkin, PINK1, and UCH-L1. We found that synphilin-1A robustly increases the steady-state levels of SIAH by decreasing its auto-ubiquitylation and degradation. In addition, synphilin-1A blocks the ubiquitylation and degradation of the SIAH substrates synphilin-1 and deleted in colon cancer protein. Furthermore, synphilin-1A strongly decreases the monoubiquitylation of alpha-synuclein by SIAH and the formation of alpha-synuclein inclusions, supporting a role for monoubiquitylation in alpha-synuclein inclusion formation. Our results suggest a novel function for synphilin-1A as a regulator of SIAH activity and formation of Lewy body-like inclusions.
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