The mechanisms of Parkinson's disease. Toxicity of Homocysteine and Genetic Polymorphism of Homocysteine-related enzymes

我们曾报道帕金森病（PD）患者存在高同型半胱氨酸血症。本研究通过对20例MTHFR C677 T基因型的原发性PD患者服用左旋多巴前后血浆同型半胱氨酸水平的测定，探讨PD患者发生高同型半胱氨酸血症的机制。20例原发性PD患者左旋多巴给药前的Hcy浓度（11.0^^+__-4.5 nmol/ml）与对照组（10.2^^+_-5.3 nmol/ml）相比无显著差异。然而，左旋多巴给药后Hcy浓度显著升高（18.8 ± 13.5 nmol/ml）。为了研究左旋多巴治疗后Hcy浓度升高与MTHFR C677 T基因型之间的关系，我们根据MTHFR基因型将患者分为三组。同型半胱氨酸浓度在C/C基因型组中从10.9^^+_-1.6增加到14.6^^+_-2.4 nmol/ml，在C/T基因型组中从10.3^^+_-4.0增加到14.1^^+_-4.2 nmol/ml，在T/T基因型组中从11.9^^+_-7.1增加到29.3^^+_-21.8 nmol/ml。此外，我们还研究了PD患者颈动脉粥样硬化的变化，因为Hcy是血管疾病的危险因素之一。超声检查显示在左旋多巴治疗的PD患者的IMC肥大。这些结果表明，左旋多巴诱导的高同型半胱氨酸血症可能导致继发性动脉粥样硬化。此外，我们还测定了同型半胱氨酸形成过程中的代谢产物S-腺苷甲硫氨酸（SAM）和S-腺苷高半胱氨酸（SAH）。PD患者治疗时间长或有逐渐消失现象者SAM/SAH比值较低。

We previously reported that the hyperhomocysteinemia was observed in patients with Parkinson's disease(PD). In this project, to clarify the mechanisms how hyperhomocysteinemia occurs in PD patients, we measured plasma homocysteine level in 20 de novo PD patients in each type of MTHFR C677T genotype before and after levodopa administration. Hcy concentrations before levodopa administration in the 20 de novo PD patients (11.0^^+__-4.5 nmol/ml) did not differ significantly as compared to control subjects (10.2^^+__-5.3 nmol/ml). However, Hcy concentrations were significantly elevated after levodopa administration(18.8^^+__-13.5 nmol/ml). In order to investigate the association between the increase in Hcy concentrations following levodopa treatment and MTHFR C677T genotype, we classified patients into three groups according to their MTHFR genotypes. Hcy concentrations were increased from 10.9^^+__-1.6 to 14.6^^+__-2.4 nmol/ml in the C/C genotype group, from 10.3^^+__-4.0 to 14.1^^+__-4.2 nmol/ml in the C/T group, and from 11.9^^+__-7.1 to 29.3^^+__-21.8 nmol/ml in the T/T group. Moreover, we investigate atheroscrlrotic change in carotid artery in PD patients, because Hcy is one of the risk factors of vascular diseases. Ultrasonography showed hypertrophy of IMC in levodopa treated PD patients. These results suggest that levodopa-induced hyperhomocysteinemia may induce secondary atherosclerosis. Furthermore, we measured S-adenosylmethionine(SAM) and S-adenosylhomocysteine(SAH), metabolites during the formation of Hcy. PD patients treated for long duration or with wearing-off phenomenon have low SAM/SAH ratio.