EXCESS BIOLOGICAL METHYLATION AND PARKINSONS DISEASE

黑质纹状体通路的变性和多巴胺的耗竭 (DA)、去甲肾上腺素（NE）、5-羟色胺（5-HT）和黑色素，以及 乙酰胆碱（Ach）活性的增加是一些生物化学反应， 帕金森病（PD）中的畸变与 震颤、运动功能减退和肌肉僵硬的症状。 增加 生物甲基化，相对于生物胺的合成， 降低DA、NE、黑色素和5-HT，升高Ach， 代谢物是已知的运动功能减退剂和细胞毒性剂， 可以想象，可以解释部分症状和神经元 帕金森症的退化 初步研究表明， 注射S-腺苷-L-甲硫氨酸（SAM），甲基供体，进入 脑引起的帕金森型运动障碍，即;震颤， 强直和运动功能减退被1-多巴抑制， 而不是d-多巴，无活性的立体异构体。 在重复的 注射SAM神经元变性和酪氨酸羟化酶（TH） 基底神经节中的消耗也被检测到，因此SAM可能是 PD的重要性。 本计画将进一步研究帕金森氏症型的运动障碍 引起的感染。 特别是，剂量谱，急性与 慢性的，和具体的药理作用剂的影响将是 考察 与DA、NE、5-HT及其代谢产物的变化进行相关性分析。 甲基化代谢物，以及胆碱和乙酰胆碱。 TH的活动 胆碱乙酰转移酶和神经元变性，形态学和 还将研究人口变化。 这些挑战将帮助我们了解SAM在以下方面的作用机制： 诱导运动和神经元畸变，并将筛选潜在的 增效剂和拮抗剂。 所产生的信息将有助于 我们对SAM的CNS药理学和毒理学的了解表明， 甲基化的增加是否会产生类似于 PD的症状 这些研究可能有助于开发一种模型， 帕金森症，从长远来看，可能会发现过量的 甲基化可能与PD相关;可能是继发性的 因子 这些数据将使我们能够为基础和 临床研究。 SAM的作用是广泛而深刻的，影响着 不仅是神经递质的代谢， 蛋白质和脂质。 作为甲基化的速率限制因素， 活动随着年龄的增长而增加，SAM的病理作用也可能是 虽然目前被低估了，但还是很深刻的。

The degeneration of the nigrostriatal pathway and depletion of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and melanin pigments, and increases in acetylcholine (Ach) activity are some of the biochemical aberrations in Parkinson's disease (PD) that are associated with the symptoms of tremors, hypokinesia and muscular rigidity. An increase in biological methylation, relative to the synthesis of the biogenicamines, should decrease DA, NE, melanin and 5-HT, increase Ach, and should produce metabolites that are known hypokinetic and cytotoxic agents that conceivably could account for part of the symptoms and the neuronal degeneration in parkinsonism. Preliminary studies showed that the injection of S-adenosyl-L-methionine (SAM), the methyl donor, into the brain caused parkinsonian-type of motor impairments, namely; tremor, rigidity and hypokinesia that were inhibited by 1-dopa, the major therapy for PD, but not d-dopa, the inactive stereoisomer. Following the repeated injections of SAM neuronal degeneration and tyrosine hydroxylase (TH) depletion in the basal ganglia were also detected, so SAM may be of importance in PD. This project will further study the parkinsonian-types of motor impairments caused by SAM in the rat. In particular, the dose spectrum, acute versus the chronic, and the effects of specific pharmacological agents will be examined. Correlation will be made with changes in DA, NE, 5-HT and their methylated metabolites, as well as choline and Ach. The activities of TH and choline acetyl transferase and neuronal degeneration, morphological and population changes will also be studied. The challenges will help us understand the mechanism of action of SAM in inducing the motor and neuronal aberrations and will screen for potential synergists and antagonists. The information generated will contribute to our knowledge of the CNS pharmacology and toxicology of SAM and show whether increased methylation will produce imbalances that resemble the symptoms of PD. The studies may help in the development of a model for parkinsonism, and in the longer terms, it might turn out that an excess of methylation may be found to be associated with PD; may be as a secondary factor. The data will allow us to develop strategy for both basic and clinical studies. The role of SAM is extensive and profound, affecting the metabolism of, not only, neurotransmitters but also RNA, DNA, membranes proteins and lipids. As a rate limiting factor in methylation, whose activities increased with aging the pathological role of SAM is also likely to be profound; although at present very under-rated.