Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1620, USA.
J Neurochem. 2013 Sep;126(5):591-603. doi: 10.1111/jnc.12345. Epub 2013 Jul 22.
Intra-neuronal metabolism of dopamine (DA) begins with production of 3,4-dihydroxyphenylacetaldehyde (DOPAL),which is toxic. According to the 'catecholaldehyde hypothesis', DOPAL destroys nigrostriatal DA terminals and contributes to the profound putamen DA deficiency that characterizes Parkinson’s disease (PD). We tested the feasibility of using post-mortem patterns of putamen tissue catechols to examine contributions of altered activities of the type 2 vesicular monoamine transporter (VMAT2) and aldehyde dehydrogenase(ALDH) to the increased DOPAL levels found in PD. Theoretically, the DA : DOPA concentration ratio indicates vesicular uptake, and the 3,4-dihydroxyphenylacetic acid: DOPAL ratio indicates ALDH activity. We validated these indices in transgenic mice with very low vesicular uptake VMAT2-Lo) or with knockouts of the genes encoding ALDH1A1 and ALDH2 (ALDH1A1,2 KO), applied these indices in PD putamen, and estimated the percent decreases in vesicular uptake and ALDH activity in PD. VMAT2-Lo mice had markedly decreased DA:DOPA (50 vs. 1377, p < 0.0001),and ALDH1A1,2 KO mice had decreased 3,4-dihydroxyphenylacetic acid:DOPAL (1.0 vs. 11.2, p < 0.0001). In PD putamen, vesicular uptake was estimated to be decreased by 89% and ALDH activity by 70%. Elevated DOPAL levels in PD putamen reflect a combination of decreased vesicular uptake of cytosolic DA and decreased DOPAL detoxification by ALDH.
多巴胺（DA）的神经元内代谢始于 3,4-二羟基苯乙醛（DOPAL）的产生，而 DOPAL 具有毒性。根据“儿茶酚醛假说”，DOPAL 破坏黑质纹状体 DA 末梢，并导致帕金森病（PD）的纹状体 DA 严重缺乏。我们测试了使用纹状体组织儿茶酚的死后模式来检查改变的 2 型囊泡单胺转运体（VMAT2）和醛脱氢酶（ALDH）的活性对 PD 中发现的 DOPAL 水平升高的贡献的可行性。理论上，DA：DOPA 浓度比表示囊泡摄取，而 3,4-二羟基苯乙酸：DOPAL 比表示 ALDH 活性。我们在囊泡摄取极低的 VMAT2 低表达（VMAT2-Lo）转基因小鼠或编码 ALDH1A1 和 ALDH2 的基因敲除（ALDH1A1,2 KO）小鼠中验证了这些指标，将这些指标应用于 PD 纹状体，并估计 PD 中囊泡摄取和 ALDH 活性的百分比降低。VMAT2-Lo 小鼠的 DA：DOPA（50 比 1377，p <0.0001）明显降低，而 ALDH1A1,2 KO 小鼠的 3,4-二羟基苯乙酸：DOPAL（1.0 比 11.2，p <0.0001）降低。在 PD 纹状体中，估计囊泡摄取降低了 89%，ALDH 活性降低了 70%。PD 纹状体中 DOPAL 水平升高反映了胞质 DA 囊泡摄取减少和 ALDH 降低 DOPAL 解毒的综合作用。
