Impaired transcriptional upregulation of Parkin promoter variant under oxidative stress and proteasomal inhibition: clinical association
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We provided data to show that the transcriptional activity of wildtype −258T in the parkin promoter region was significantly higher than the −258G variant in human cell lines. The transcriptional activity of wildtype −258T was significantly increased under oxidative stress by hydrogen peroxide, but this was not observed for the −258G variant. The transcriptional upregulation was significantly higher for wildtype −258T compared to −258G variant at 0.1, 0.2 and 0.4 mM of hydrogen peroxide. Similar results were obtained when the cells were treated with a proteasome inhibitor, MG132.
Furthermore, in a case control study involving 753 subjects, we demonstrated that the parkin promoter −258G variant was associated with an increased risk of sporadic Parkinson’s disease (PD) in the elderly ethnic Chinese population. Our clinical and laboratory data provide corroborative evidence that some older individuals who have the −258G variant may have a higher risk of developing PD.
KeywordsParkin Proteasomal Inhibition Transcriptional Upregulation Firefly Luciferase Reporter Aging Neuron
The study was supported by grants from the National Medical Research Council and Department of Clinical Research, Singapore General Hospital. The authors thank the directors of National Neuroscience Institute and SingHealth Research and Dr. AW Swee Eng for his support.
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