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Updated: Jul 10, 2026
Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease
Published on: January 7, 2014
MPTP administration in mice changes the ratio of splice isoforms of fosB and rgs9
Judith A Potashkin1, Un Jung Kang, Patricia A Loomis
1Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA. judy.potashkin@rosalindfranklin.edu
Abstract:
Most cases of Parkinson's disease (PD) are sporadic, suggesting an environmental influence on individuals affected by this neurodegenerative disorder. Environmental stresses often lead to changes in the regulation of splicing of pre-mRNA transcripts and this may lead to the pathogenesis of the disease. A 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid mouse model was used to examine the changes in the splicing of the fosB and rgs9 transcripts. The ratio of DeltafosB/fosB transcript was decreased in the substantia nigra and unchanged in the striatum after acute MPTP treatment. The DeltafosB/fosB transcript ratio decreased initially and then increased in the striatum of chronically MPTP-treated animals due to different degrees of reduction for the splice variants over time, whereas the ratio was unchanged in the substantia nigra. The ratio of rgs9-2/rgs9-1 transcript decreased in the substantia nigra of mice after acute MPTP treatment and increased temporarily in the striatum after chronic MPTP treatment. There was an increase in the DeltaFosB/FosB and RGS9-2/RGS9-1 protein ratios 3 weeks and 3 days post-treatment, respectively, in chronically treated mice. The data indicate that the pattern of splice isoforms of fosB and rgs9 reflects the brain's immediate and long-term responses to the physiological stress associated with Parkinsonism.
Insights
Environmental factors may trigger Parkinson's disease (PD) by altering gene splicing. This study observed changes in fosB and rgs9 splicing patterns in a mouse model, reflecting the brain's stress response to Parkinsonism.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Parkinson's disease (PD) is a neurodegenerative disorder with sporadic origins, suggesting environmental factors play a role.
- Environmental stresses can disrupt pre-mRNA splicing, potentially contributing to PD pathogenesis.
- Investigating gene splicing alterations offers insights into the molecular mechanisms underlying PD.
Purpose of the Study:
- To examine changes in the splicing of fosB and rgs9 transcripts in a mouse model of Parkinson's disease.
- To understand how acute and chronic environmental stress affects splice variant ratios in different brain regions.
- To correlate changes in transcript splicing with protein level alterations.
Main Methods:
- Utilized a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid mouse model to induce Parkinsonism.
- Analyzed the splicing patterns of fosB and rgs9 transcripts in the substantia nigra and striatum.
- Measured protein ratios of DeltaFosB/FosB and RGS9-2/RGS9-1 post-MPTP treatment.
Main Results:
- Acute MPTP treatment decreased the DeltafosB/fosB transcript ratio in the substantia nigra.
- Chronic MPTP treatment induced dynamic changes in DeltafosB/fosB ratios in the striatum and increased DeltaFosB/FosB and RGS9-2/RGS9-1 protein ratios.
- MPTP exposure altered rgs9-1 and rgs9-2 transcript ratios in both acute and chronic models.
Conclusions:
- The splicing patterns of fosB and rgs9 are sensitive indicators of the brain's response to Parkinsonism-associated stress.
- Alterations in splice isoforms reflect both immediate and long-term physiological adaptations to neurotoxic insults.
- These findings highlight the role of pre-mRNA splicing dysregulation in the pathogenesis of Parkinson's disease.
