ArticleeNeuro
The SUMO Conjugase Ubc9 Protects Dopaminergic Cells from Cytotoxicity and Enhances the Stability of α-Synuclein in Parkinson's Disease Models.
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Who cites it
12 citing papers in PubMed, 15 citations in OpenAlex.
- Article
- The role of SUMOylation in regulating proteins that drive neuronal disease progression.Biochemistry and biophysics reports · 2026Review
- SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.Molecular neurobiology · 2026Review
- Organelle regulation of SUMOylation: regulatory mechanisms and therapeutic application.Journal of advanced research · 2026Review
- UBC9 mediates mitophagy to attenuate oxidative stress by regulating SUMOylation of PINK1 in the Parkinson's disease progression.Cell biology and toxicology · 2025Article
- Screening, identification, and experimental validation of SUMOylation biomarkers in Parkinson's disease.Hereditas · 2025Article
- Posttranslational Modifications ofPharmacological reviews · 2024Review
- The regulation of NFKB1 on CD200R1 expression and their potential roles in Parkinson's disease.Journal of neuroinflammation · 2024Article
- Genetic modifiers of synucleinopathies-lessons from experimental models.Oxford open neuroscience · 2023Review
- A Novel NOX Inhibitor Treatment Attenuates Parkinson's Disease-Related Pathology in Mouse Models.International journal of molecular sciences · 2022Article
- Alpha-Synuclein Preformed Fibrils Induce Cellular Senescence in Parkinson's Disease Models.Cells · 2021Article
- Modulation of the Interactions Between α-Synuclein and Lipid Membranes by Post-translational Modifications.Frontiers in neurology · 2021Review
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
Small ubiquitin-like modifier (SUMO) is a widespread regulatory mechanism of post-translational modification (PTM) that induces rapid and reversible changes in protein function and stability. Using SUMO conjugase Ubc9-overexpressing or knock-down cells in Parkinson's disease (PD) models, we demonstrate that SUMOylation protects dopaminergic cells against MPP+ or preformed fibrils (PFFs) of α-synuclein (α-syn)-induced toxicities in cell viability and cytotoxicity assays. In the mechanism of protection, Ubc9 overexpression significantly suppressed the MPP+ or PFF-induced reactive oxygen species (ROS) generation, while Ubc9-RNAi enhanced the toxicity-induced ROS production. Further, PFF-mediated protein aggregation was exacerbated by Ubc9-RNAi in thioflavin T staining, compared with NC1 controls. In cycloheximide (Chx)-based protein stability assays, higher protein level of α-syn was identified in Ubc9-enhanced green fluorescent protein (EGFP) than in EGFP cells. Since there was no difference in endogenous mRNA levels of α-syn between Ubc9 and EGFP cells in quantitative real-time PCR (qRT-PCR), we assessed the mechanisms of SUMO-mediated delayed α-syn degradation via MG132, proteasomal inhibitor, and PMA, lysosomal degradation inducer. Ubc9-mediated SUMOylated α-syn avoided PMA-induced lysosomal degradation because of its high solubility. Our results suggest that Ubc9 enhances the levels of SUMO1 and ubiquitin on α-syn and interrupts SUMO1 removal from α-syn. In immunohistochemistry, dopaminergic axon tips in the striatum and cell bodies in the substantia nigra from Ubc9-overexpressing transgenic mice were protected from MPTP toxicities compared with wild-type (WT) siblings. Our results support that SUMOylation can be a regulatory target to protect dopaminergic neurons from oxidative stress and protein aggregation, with the implication that high levels of SUMOylation in dopaminergic neurons can prevent the pathologic progression of PD.
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