Smeyne Michelle, Boyd Justin, Raviie Shepherd Kennie, Jiao Yun, Pond Brooks Barnes, Hatler Matthew, Wolf Roland, Henderson Colin, Smeyne Richard Jay
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1977-82. doi: 10.1073/pnas.0610978104. Epub 2007 Jan 31.
The cause of 95% of Parkinson's disease (PD) cases is unknown. It is hypothesized that PD arises from an interaction of free-radical-generating agents with an underlying genetic susceptibility to these compounds. Here we use the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of parkinsonism to examine the role of a dual function protein, GSTpi, in dopaminergic neuron death. GSTpi is the only GST family member expressed in substantia nigra neurons. GSTpi reduction by pharmacological blockade, RNA inhibition, and gene targeting increases sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, suggesting that differential expression of GSTpi contributes to the sensitivity to xenobiotics in the substantia nigra and may influence the pathogenesis of reactive oxygen species-induced neurological disorders including PD.
95%的帕金森病(PD)病例病因不明。据推测,PD源于产生自由基的物质与对这些化合物的潜在遗传易感性之间的相互作用。在此,我们使用帕金森病的1-甲基-4-苯基-1,2,3,6-四氢吡啶模型来研究双功能蛋白谷胱甘肽S-转移酶π(GSTpi)在多巴胺能神经元死亡中的作用。GSTpi是黑质神经元中唯一表达的谷胱甘肽S-转移酶家族成员。通过药理学阻断、RNA抑制和基因靶向降低GSTpi会增加对1-甲基-4-苯基-1,2,3,6-四氢吡啶的敏感性,这表明GSTpi的差异表达导致黑质对外源物质的敏感性,并可能影响包括PD在内的活性氧诱导的神经疾病的发病机制。