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Selective alterations of transcription factors in MPP+-induced neurotoxicity in PC12 cells
Z Xu1, D Cawthon, K A McCastlain
1Neurochemistry Laboratory, Division of Neurotoxicology, HFT-132, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA.
Abstract:
MPP(+) (1-methyl-4-phenylpyridinium; the active metabolite of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine)) depletes dopamine (DA) content and elicits cell death in PC12 cells. However, the mechanism of MPP(+)-induced neurotoxicity is still unclear. In this study, the dose response and time-course of MPP(+)-induced DA depletion and decreased cell viability were determined in nerve growth factor (NGF)-differentiated PC12 cells. The alteration of transcription factors (TFs) induced by MPP(+) from a selected dose level and time point was then evaluated using protein/DNA-binding arrays. K-means clustering analysis identified four patterns of protein/DNA-binding changes. Three of the 28 TFs identified in PC12 cells increased by 100% (p53, PRE, Smad SBE) and 2 decreased by 50% (HSE, RXR(DR1)) of control with MPP(+) treatment. In addition, three TFs decreased within the range of 33-50% (TFIID, E2F1, CREB) and two TFs increased within the range of 50-100% (PAX-5, Stat4). An electrophoretic mobility shift assay (EMSA) was used to confirm the changes of p53 and HSE. The observed changes in TFs correlated with the alterations of DA and cell viability. The data indicates that selective transcription factors are involved in MPP(+)-induced neurotoxicity and it provides mechanistic information that may be applicable to animal studies with MPTP and clinical studies of Parkinson's disease.
Insights
1-methyl-4-phenylpyridinium (MPP(+)) causes neurotoxicity by altering transcription factors (TFs) in PC12 cells. These TF changes correlate with dopamine depletion and cell death, offering insights into Parkinson's disease mechanisms.
Area of Science:
- Neuroscience
- Molecular Biology
- Toxicology
Background:
- 1-methyl-4-phenylpyridinium (MPP(+)), the active metabolite of MPTP, is known to cause neurotoxicity.
- MPP(+)-induced neurotoxicity mechanisms, particularly involving transcription factor alterations, remain unclear.
- PC12 cells, differentiated with nerve growth factor (NGF), serve as a model for studying neurotoxicity.
Purpose of the Study:
- To investigate the dose-response and time-course of MPP(+)-induced dopamine (DA) depletion and cell death in NGF-differentiated PC12 cells.
- To identify and evaluate alterations in transcription factors (TFs) following MPP(+) treatment.
- To correlate changes in TF activity with observed neurotoxic effects.
Main Methods:
- Dose-response and time-course studies of MPP(+) on DA content and cell viability in PC12 cells.
- Protein/DNA-binding arrays to assess alterations in 28 TFs after MPP(+) exposure.
- K-means clustering to identify patterns of TF binding changes.
- Electrophoretic mobility shift assay (EMSA) to validate changes in specific TFs (p53, HSE).
Main Results:
- MPP(+) treatment led to dose- and time-dependent DA depletion and decreased cell viability.
- Significant alterations in the binding activity of several TFs were observed, including increases in p53, PRE, Smad SBE, PAX-5, and Stat4, and decreases in HSE, RXR(DR1), TFIID, E2F1, and CREB.
- Changes in TF activity correlated with the extent of DA depletion and cell death.
- EMSA confirmed the array findings for p53 and HSE.
Conclusions:
- Selective transcription factors are demonstrably involved in MPP(+)-induced neurotoxicity.
- The identified TF alterations provide mechanistic insights into MPP(+)-induced neuronal damage.
- Findings may inform future animal studies using MPTP and clinical research on Parkinson's disease.
