Mechanisms of Parkinson Disease and Related Disorders

我们获得的证据表明，遗传性突触核病，由于编码α-突触核蛋白的基因突变或正常基因的三重，不仅会导致家族性帕金森综合征，还会导致心脏交感神经失神经。我们的神经影像发现已经被尸检病理证实，显示有突触核蛋白基因重复的患者的心外膜神经中酪氨酸羟基酶免疫反应性显著降低。根据对偶发性路易体病心脏神经中α-突触核蛋白和酪氨酸羟基酶免疫反应性的研究，发现在交感神经节中有一个向心性的逆行失神经过程，首先是心肌远端α-突触核蛋白沉积和含酪氨酸羟基酶的神经丢失，然后是交感神经节更近端的病变和路易体的形成。最终，在临床明显的帕金森病患者，心脏中没有可检测到的α-突触核蛋白沉积，这可能是因为缺乏去甲肾上腺素能神经，主要病理结果是心外膜神经酪氨酸羟基酶缺失和神经节细胞路易小体的存在。与向心性的逆行过程一致，后续的神经成像研究显示，左心室心尖部和下外侧壁6-18F-氟多巴胺衍生的放射性早期、进行性丧失，后期失去更多前基前间隔近端的放射性。 为了更好地了解α-突触核病和儿茶酚胺能神经丧失之间的联系，我们正在测试源于细胞质胺是自体毒素这一概念的假说。其他小组关注的是细胞质胺的自氧化，而我们关注的是酶的自毒作用。根据儿茶醛假说，细胞质中的多巴胺被线粒体单胺氧化酶转化为有毒的儿茶醛，即二羟基苯乙醛(DOPAL)。DOPAL被乙醛脱氢酶(ALDH)解毒，生成二羟基苯乙酸(DOPAC)。使用一种同时检测DOPAL、DOPAC和多巴胺的新方法，我们发现在终末期PD患者的壳核中，每个多巴胺末端的DOPAL估计量约为对照组的10倍，ALDH活性(以DOPAC/DOPAL比率衡量)约为对照组的25%。这些显著的发现与帕金森病患者壳核ALDH活性降低所致的DOPAL积聚一致。 综上所述，帕金森病患者大脑和心脏中儿茶酚胺能神经功能丧失与阿尔法-突触核病有关，死后帕金森病患者的脑部表现为DOPAL积聚和ALDH活性降低。在未来，我们希望开发细胞和动物模型，从实验上测试帕金森病是否由儿茶酚醛和α-突触核蛋白之间的病理性相互作用引起。

We obtained evidence that inherited synucleinopathy, from mutation of the gene encoding alpha-synuclein or from triplication of the normal gene, results not only in familial parkinsonism but also in cardiac sympathetic denervation. Our neuroimaging findings have been confirmed by post-mortem pathology demonstrating markedly decreased tyrosine hydroxylase immunoreactivity in epicardial nerves from patients with synuclein gene duplication. Based on studies of alpha-synuclein and tyrosine hydroxylase immunoreactivity in cardiac nerves in incidental Lewy body disease (thought to represent pre-symptomatic PD), there appears to be a centripetal, retrograde denervation process, beginning with alpha-synuclein deposition and loss of tyrosine hydroxylase-containing nerves in distal myocardium, followed by more proximal lesions and formation of Lewy bodies in sympathetic ganglia. Eventually, in clinically overt PD, there is no detectable alpha-synuclein deposition in the heart, presumably because of absence of noradrenergic nerves, and the main pathologic findings are absence of epicardial neural tyrosine hydroxylase and presence of ganglionic Lewy bodies. Consistent with a centripetal, retrograde process, follow-up neuroimaging studies have shown early, progressive loss of 6-18Ffluorodopamine-derived radioactivity in the apex and inferolateral walls of the left ventricle, with later loss of more proximal anterobasal septal radioactivity. To understand better the link between alpha-synucleinopathy and catecholaminergic denervation, we are testing hypotheses derived from the concept that cytoplasmic amines are autotoxins. Whereas other groups are focusing on auto-oxidation of cytoplasmic amines, we are focusing on enzymatic autotoxicity. According to the catecholaldehyde hypothesis, cytoplasmic dopamine is converted by mitochondrial monoamine oxidase to the toxic catecholaldehyde, dihydroxyphenylacetaldehyde (DOPAL). DOPAL is detoxified by aldehyde dehydrogenase (ALDH), to form dihydroxyphenylacetic acid (DOPAC). Using a novel assay method for measuring DOPAL, DOPAC, and dopamine simultaneously, we found that in the putamen of patients with end-stage PD the estimated amount of DOPAL per dopamine terminal was about 10 times control, and ALDH activity, measured by the DOPAC:DOPAL ratio, was about 25% of control. These striking findings are consistent with DOPAL buildup from decreased ALDH activity in the putamen of PD patients. In summary, in PD catecholaminergic denervation in the brain and heart is linked to alpha-synucleinopathy, and post-mortem PD brain features DOPAL buildup and decreased ALDH activity. In the future we hope to develop cellular and animal models to test experimentally whether PD results from pathologic interactions between catecholaldehydes and alpha-synuclein.