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Published on: January 7, 2014
Time course of MPTP toxicity on translational control protein expression in mice brain
Julie Deguil1, François Chavant, Claire Lafay-Chebassier
1Research Group on Brain Aging, GReViC, EA 3808, Pôle de Biologie Santé, 40 avenue du Recteur Pineau, 86022 POITIERS cedex, France.
Abstract:
The present study investigated in mice brain, the time course of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity on the expression of translational control proteins. Mice received intraperitoneal injections of MPTP (30 mg/kg/day) for 5 days and were sacrificed 1, 2, 3, 4 and 7 days after the last injection. The results, obtained by western blot, indicated that MPTP produced an alteration of the expression of proteins involved in the mTOR anti-apoptotic way and the PKR pro-apoptotic pathway of translational control especially in striatum and frontal cortex of mice. These disturbances were associated with a great activation of PKR in hippocampus at D9, the time point corresponding to maximal translational control alterations. Furthermore, whereas no modification of translational control protein expression was observed in mice substantia nigra after western blot procedure, immunofluorescent labeling revealed, in this target region of the toxin MPTP, a decrease of the expression of phospho-mTOR and a great activation of the phosphorylated form of PKR, marker of pathogenesis.
Insights
This study shows how 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) affects proteins controlling cell growth and death in mouse brains. MPTP alters key pathways, impacting brain regions like the striatum and frontal cortex.
Area of Science:
- Neuroscience
- Molecular Biology
- Toxicology
Background:
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin used to model Parkinson's disease.
- Translational control proteins regulate protein synthesis and are crucial for cellular function and survival.
- Dysregulation of these pathways is implicated in neurodegenerative diseases.
Purpose of the Study:
- To investigate the time-dependent effects of MPTP toxicity on the expression of translational control proteins in the mouse brain.
- To identify specific pathways (mTOR and PKR) affected by MPTP exposure.
- To correlate changes in protein expression with MPTP-induced neuropathology.
Main Methods:
- Mice were administered MPTP (30 mg/kg/day) intraperitoneally for 5 days.
- Brain tissues (striatum, frontal cortex, hippocampus, substantia nigra) were collected at 1, 2, 3, 4, and 7 days post-injection.
- Western blot analysis was used to assess protein expression levels.
- Immunofluorescent labeling was employed to visualize protein localization and activation in specific brain regions.
Main Results:
- MPTP altered the expression of proteins in the mTOR (anti-apoptotic) and PKR (pro-apoptotic) translational control pathways, particularly in the striatum and frontal cortex.
- PKR activation was significantly increased in the hippocampus at day 9, coinciding with maximal translational control disturbances.
- While western blot showed no changes in the substantia nigra, immunofluorescence revealed decreased phospho-mTOR and increased phosphorylated PKR in this critical region.
Conclusions:
- MPTP neurotoxicity induces significant alterations in key translational control pathways (mTOR and PKR) in a time- and region-dependent manner.
- These molecular disturbances, including PKR activation and mTOR inhibition, are associated with MPTP-induced pathogenesis in specific brain areas.
- The findings highlight the role of translational control dysregulation in MPTP-induced neurotoxicity, potentially offering insights into Parkinson's disease mechanisms.
