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）选择性摄取其代谢物MPP +进入多巴胺能神经元后，可引起人类和灵长类动物的帕金森综合征。MPP +沿电化学梯度向线粒体内富集，选择性且有效地抑制电子传递链的复合物- 1。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。为了确定帕金森病的机制，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大脑中NF-kB核易位上调。为了确定NF-kB的作用，我们通过Ik-B的过表达调节其核内易位。一个超级抑制因子IkB在32和36残基上有丝氨酸到丙氨酸的突变，这抑制了它的磷酸化。我们利用腺病毒将超抑制因子IkB基因过表达到神经元中。与模拟感染处理的MPP+诱导细胞死亡率相比，Ad-Ik-B处理显著降低MPP+诱导细胞死亡率。涉及caspase 1和caspase 11的级联反应可能是病理状态下神经元细胞死亡的常见途径之一。将MPTP立体定向注射到caspase 11ko小鼠纹状体中。这是小鼠的TH染色。此图为MPTP治疗的caspase 11 KO小鼠。这是一只接受过MPTP治疗的正常小鼠。图为MPTP处理的caspase 11 KO小鼠。Caspase 11ko小鼠可预防MPTP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.