GST P1, a novel downstream regulator of LRRK2, G2019S-induced neuronal cell death
| Autor: | Jie, Chen, Anthony, Liou, Lili, Zhang, Zhongfang, Weng, Yanqin, Gao, Guodong, Cao, Michael J, Zigmond, Jun, Chen |
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| Rok vydání: | 2012 |
| Předmět: |
Programmed cell death
Blotting Western Protein Serine-Threonine Kinases medicine.disease_cause urologic and male genital diseases Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Real-Time Polymerase Chain Reaction General Biochemistry Genetics and Molecular Biology Article Tandem Mass Spectrometry Cell Line Tumor medicine Humans Fluorescent Antibody Technique Indirect neoplasms DNA Primers Glutathione Transferase Neurons Gene knockdown General Immunology and Microbiology Base Sequence Cell Death Chemistry Neurotoxicity medicine.disease LRRK2 Molecular biology Cell biology nervous system diseases Cell culture Apoptosis Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization Electrophoresis Polyacrylamide Gel Signal transduction Oxidative stress |
| Zdroj: | Frontiers in bioscience (Elite edition). 4(7) |
| ISSN: | 1945-0508 |
| Popis: | The enhanced neurotoxicity of the Parkinson’s disease-associated LRRK2 mutant, G2019S, than its wild-type counter-part has recently been reported. Overexpression of LRRK2 (G2019S) in cultured neural cells results in caspase-3-dependent apoptosis via a yet undefined signaling pathway. Elucidation of the mechanism underlying LRRK2 (G2019S) neurotoxicity may offer new insights into the pathogenesis of Parkinson’s disease. In this study, utilizing two-dimensional gel electrophoresis coupled with mass spectrometry, we have identified glutathione s-transferase P1 (GSTP1) as a selective target whose expression is negatively regulated at the transcriptional levels by LRRK2 (G2019S). Overexpression of LRRK2 (G2019S) in the human neuronal cell line SH-SY5Y markedly suppressed the expression of GSTP1 prior to any manifestation of cell death. This suppression of GSTP1 expression was due to LRRK2 (G2019S) – elicited production of peroxides and subsequent hyper-methylation on the promoter of GSTP1. Moreover, shRNA-mediated knockdown of endogenous GSTP1 expression exacerbated LRRK2 (G2019S) neurotoxicity, whereas overexpression of GSTP1 protected against LRRK2 (G2019S)-induced caspase-3 activation and neuronal apoptosis. In conclusion, the results suggest a previously undefined signaling mechanism underlying the neurotoxic effect of LRRK2 (G2019S), in which LRRK2 (G2019S) triggers oxidative stress in cells and, in turn, results in caspase-dependent apoptosis at least in part by suppressing the expression of GSTP1. |
| Databáze: | OpenAIRE |
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