MOLECULAR GENETIC ANALYSIS OF S ADENOSYL L METHIONINE IN PARKINSONS DISEASE

帕金森病（PD）是一种神经退行性疾病，其特征在于 各种运动功能的失控。 的主要标志 帕金森病是指大脑中含有多巴胺的细胞体的变性， 大脑和神经递质多巴胺（DA）的损失。 建立 黑质纹状体神经元退化和黑质纹状体神经元减少的分子基础 DA生产是开发有效的选择性药物的关键， PD的治疗干预。 最近的体内研究表明S- 腺苷-L-甲硫氨酸（SAM）在PD的病理生理学。 注射SAM 会引起病理和行为变化， 类似于PD患者中观察到的情况。 病理变化包括 黑质神经元的退化 初步数据显示 SAM处理后，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 调节TH的表达，这种酶催化的速率- DA生物合成的限制步骤。 如果是这样的话， 脑内SAM可触发TH基因表达的变化， 可能导致DA耗竭和神经元细胞变性。 项目 将利用分子方法来研究 SAM对TH基因表达的影响。 来自SAM处理的脑组织匀浆和 使用RT-PCR方法分析对照大鼠的TH mRNA水平。 SAM对TH mRNA转录的调节可能表明TH是一种重要的细胞因子。 参与SAM诱导的DA耗竭。 免疫化学研究也将 以确定SAM是否也影响TH mRNA翻译。 从这些研究中获得的结果将提供深入了解 SAM在PD大鼠模型中清除DA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.