MOLECULAR GENETIC ANALYSIS OF S ADENOSYL L METHIONINE IN PARKINSONS DISEASE

帕金森病是一种神经退行性疾病，其特征是 失去对各种运动功能的控制。的主要标志 帕金森病是脑内含多巴胺的细胞体的变性。 大脑和神经递质多巴胺(DA)的丧失。建立一个 黑质纹状体神经元退化的分子基础 DA的生产是开发有效的、选择性的药物的关键 帕金森病的治疗性干预。最近的活体研究表明，S- 腺苷-L-蛋氨酸在帕金森病病理生理中的作用注射用SAM 进入大鼠的大脑导致病理和行为变化， 与帕金森病患者相似。这些病理变化包括 黑质神经元的退化。初步数据显示 在SAM治疗后，酪氨酸羟化酶(TH)- 观察到含有纤维，这伴随着 黑质TH免疫反应。这些结果表明，SAM可能 正在调节TH的表达，TH是催化速率- DA生物合成的限制步骤。如果是这种情况，则 大脑中的SAM可能会引发TH基因表达的变化，进而 可能导致DA耗竭和神经细胞变性。该项目 将利用分子方法来研究 萨姆对TH基因表达的看法。SAM处理的脑组织匀浆和 对照大鼠将使用RT-PCR方法分析TH mRNA水平。 SAM对TH基因转录的调节可能提示TH是 参与SAM引起的DA耗竭。免疫化学研究也将 以确定SAM是否也影响TH mRNA的翻译。 从这些研究中获得的结果将提供对 SAM在帕金森病大鼠模型中清除多巴胺的作用机制

Parkinson's diseases (PD) is a neurodegenerative disorder characterized by the loss of control of a variety of motor functions. The major markers of PD have been the degeneration of dopamine-containing cell bodies in the brain and the loss of the neurotransmitter dopamine (DA). Establishing a molecular basis for nigrostriatal neuronal degradation and the decrease in DA production is pivotal to developing potent, selective agents for therapeutic intervention in PD. Recent in vivo studies have implicated S- adenosyl-L-methionine (SAM) in the pathophysiology of PD. Injection of SAM into the brain of rats induces pathological and behavioral changes that resemble those observed in PD patients. The pathological changes include degradation of neurons in the substantia nigra. Preliminary data indicate that following SAM treatment, degeneration of tyrosine hydroxylase (TH)- containing fibers is observed and this is accompanied by a decrease in substantia nigra TH immunoreactivity. These results suggest that SAM might be modulating the expression of TH, the enzyme which catalyzes the rate- limiting step for DA biosynthesis. If this is the case, then elevation of SAM in the brain could trigger changes in TH gene expression, which in turn might lead to DA depletion and neuronal cell degenerations. The project will utilize a molecular approach to investigate the possible effects of SAM on TH gene expression. Brain tissue homogenates from SAM-treated and control rats will be analyzed for TH mRNA levels using an RT-PCR method. Modulation of TH mRNA transcription by SAM could suggest that TH is involved in SAM-induced DA depletion. Immunochemical studies will also be carried out to determine whether SAM also affects TH mRNA translation. Results obtained from these studies will provide insights into the mechanism of SAM's action in depleting DA in the rat model for PD.