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Published on: October 6, 2017
TCDD induces UbcH7 expression and synphilin-1 protein degradation in the mouse ventral midbrain
Emmanuel González-Barbosa1, Alejandro Mejía-García1, Elizabeth Bautista2
1Departamento de Biología Celular, CINVESTAV-IPN, México D.F, México.
Abstract:
UbcH7 is an ubiquitin-conjugating enzyme that interacts with parkin, an E3 ligase. The UbcH7-parkin complex promotes the ubiquitination and degradation of several proteins via the 26S proteasome. Cellular accumulation of the UbcH7-parkin targets alpha-synuclein and synphilin-1 has been associated with Parkinson disease. In mouse liver, 2,3,7,8-tetrachlorodibenzo-p-dioxin, an aryl hydrocarbon receptor ligand, induces UbcH7 expression. Therefore, the aim of the present study was to determine whether 2,3,7,8-tetrachlorodibenzo-p-dioxin induces Ubch7 mRNA and UbcH7 protein expression in the mouse brain, to characterize the molecular mechanism, and the effect on synphilin-1 half-life. We found that 2,3,7,8-tetrachlorodibenzo-p-dioxin promotes the aryl hydrocarbon receptor binding to Ubch7 gene promoter as well as its transactivation, resulting in an induction of UbcH7 levels in the olfactory bulb, ventral midbrain, hippocampus, striatum, cerebral cortex, brain stem, and medulla oblongata. In parallel, 2,3,7,8-tetrachlorodibenzo-p-dioxin promoted synphilin-1 degradation in an aryl hydrocarbon receptor-dependent way.
Insights
2,3,7,8-tetrachlorodibenzo-p-dioxin increases UbcH7 enzyme levels in the mouse brain, impacting synphilin-1 protein degradation. This aryl hydrocarbon receptor-dependent mechanism may influence Parkinson disease-related pathways.
Area of Science:
- Neuroscience
- Toxicology
- Molecular Biology
Background:
- UbcH7 is an ubiquitin-conjugating enzyme that interacts with parkin, an E3 ligase, promoting protein degradation.
- Accumulation of UbcH7 targets like alpha-synuclein and synphilin-1 is linked to Parkinson disease.
- 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces UbcH7 expression in mouse liver.
Purpose of the Study:
- To investigate TCDD's effect on UbcH7 mRNA and protein expression in the mouse brain.
- To elucidate the molecular mechanism of TCDD-induced UbcH7 expression.
- To determine TCDD's impact on synphilin-1 protein half-life.
Main Methods:
- Quantitative analysis of UbcH7 mRNA and protein levels in various mouse brain regions.
- Assessment of aryl hydrocarbon receptor (AhR) binding to the UbcH7 gene promoter.
- Measurement of synphilin-1 protein degradation rates.
Main Results:
- TCDD induced UbcH7 mRNA and protein expression across multiple brain regions, including the olfactory bulb, hippocampus, and striatum.
- TCDD promoted AhR binding to the UbcH7 gene promoter, leading to its transactivation.
- TCDD accelerated synphilin-1 degradation in an AhR-dependent manner.
Conclusions:
- TCDD upregulates UbcH7 expression in the mouse brain via AhR-mediated transcriptional activation.
- The induction of UbcH7 by TCDD leads to enhanced degradation of synphilin-1.
- These findings suggest a potential link between TCDD exposure, UbcH7 regulation, and Parkinson disease-associated protein processing.
