Research for the pathogenesis of Parkinson's disease (microdyalisi study for neurotxin)

神经毒素N-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)在其代谢产物MPP选择性地被多巴胺能神经元摄取后，在人类和灵长类动物中引起帕金森综合征。MPP沿着电化学梯度向下聚集到线粒体中，并选择性和有效地抑制电子传输链的复合体-I。散发性帕金森病(PD)以氧化应激为特征，具体涉及电子传递链复合体I的缺陷。为了明确帕金森病的发病机制，我们探讨了MPTP在帕金森病模型中的可能参与。最近，Hunt博士发现死后帕金森病患者脑组织中核转录因子-kB的核转位上调。为了确定核因子-kB的作用，我们通过过表达Ik-B来调节其核内转位。超级阻遏蛋白IKB在第32和36位残基有丝氨酸到丙氨酸的突变，这抑制了它的磷酸化。我们使用腺病毒将抑制因子IKB基因过表达到神经元中。与模拟感染相比，Ad-Ik-B可显著降低MPP诱导的细胞死亡率，caspase1和caspase11的级联作用可能是病理状态下神经细胞死亡的共同途径之一。我们将MPTP立体定向注射到caspase11KO小鼠的纹状体内。这显示了小鼠的染色。这张图片是一只未经MPTP处理的caspase 11 KO小鼠。这张照片是一只MPTP处理过的正常小鼠。这张图片是一只MPTP处理过的caspase 11 KO小鼠。Caspase11KO小鼠可防止MPTP的细胞死亡。

The neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine (MPTP) causes a parkinsonian syndrome in humans and primates after selective uptake of its metabolite MPP + into dopaminergic neurons. MPP + is concentrated into mitochondria down the electrochemical gradient, and selectively and potently inhibits complex-I of the electron transport chain. Sporadic Parkinson's disease (PD) is characterized by oxidative stress and specifically involves a defect in complex I of the electron transport chain. To identift the mechanism of PD, we explore the possible involvement of the MPTP in PD modelsRecently, Dr.Hunt showed the upregulation of the nuclear translocation of NF-kB in the postmortem Parkinsonian brain. To identify the role of NF-kB, we regulated its intranuclear translocation by overexpression of Ik-B.A super repressor IkB has serine-to-alanine mutations in residues 32 and 36, which inhibit its phosphorylation. We used adenovirus to overexpress the supper repressor IkB gene into the neuron. Ad-Ik-B treatment significantly decreased the ratio of MPP+ induced cell death compared with the ratio of MPP+ induced cell death treated with a Mock infection.The cascade involving caspase 1 and caspase 11 may be one of the common pathways for neuronal cell death in pathological condition. We stereotactically injected MPTP into the striatum of caspase 11 KO mice. This shows TH staining of the mice. This picture is a MPTP untreated caspase 11 KO mouse. This picture is a MPTP treated normal mouse. This picture is a MPTP treated caspase 11 KO mouse. Caspase 11 KO mice prevent the cell death of MPTP.