Mechanisms of Parkinson Disease and Related Disorders

两个普遍的假设正在推动临床神经心脏病学部分(CNCS)关于帕金森病(PD)和相关疾病的机制的研究。第一，儿茶酚胺能神经支配反映了神经末梢的发芽和丢失之间的平衡，失衡导致儿茶酚胺系统的神经退行性疾病。第二种是神经元轴浆中儿茶酚胺的积聚导致细胞程序性死亡(细胞凋亡)。在儿茶酚胺能细胞中，我们正在验证儿茶酚醛假说。根据这一假说，神经元胞浆中的儿茶酚胺通过单胺氧化酶(MAO)转化为细胞毒性的儿茶酚醛。在具有多巴胺能和去甲肾上腺素能表型的小鼠嗜铬细胞瘤细胞(MPC)中，我们已经获得了利血平诱导细胞凋亡的初步证据，利血平可以阻断囊泡型单胺转运体并增加细胞质中儿茶酚胺的浓度。由于帕金森病的特征是路易小体，即含有聚集的α-突触核蛋白的细胞质内含体，而且遗传性α-突触核病症可导致家族性帕金森病，我们对儿茶酚醛和α-突触核蛋白之间的相互作用特别感兴趣。我们最近获得的初步证据表明，DA的儿茶醛，二羟基苯乙醛(DOPAL)寡聚α-突触核蛋白，将正常可溶的蛋白质转化为潜在的致病形式。 随着斑马鱼儿茶酚胺能神经元发育领域的资深研究员海王星·米兹拉希博士的加入，我们计划研究成年斑马鱼心脏去甲肾上腺素能神经的发育以及基因表达或环境暴露对神经营养和神经退化平衡的影响，作为一种潜在的以帕金森病为特征的中枢和外周儿茶酚胺能去神经支配的动物模型。我们将检验儿茶酚醛假说，检验在MPC中，MAO抑制是否阻止利血平诱导的细胞凋亡，其方式与儿茶酚醛生成量减少相关。随着在α-突触核蛋白领域经验丰富的研究员Nelson Cole博士的加入，我们将在细胞和动物模型中研究α-突触核蛋白-儿茶酚胺的相互作用，DOPAL被乙醛脱氢酶(AD)解毒，并利用液相色谱-串联质谱仪(LC/MS/MS)，我们希望识别AD活性降低的PD患者。儿茶酚胺代谢异常图谱的识别应促进假说驱动的基因组、蛋白质组和活检研究，阐明帕金森病和相关疾病的机制。

Two general hypotheses are driving research of the Clinical Neurocardiology Section (CNCS) about mechanisms of Parkinson disease (PD) and related disorders. The first is that catecholaminergic innervation reflects a balance between sprouting and loss of nerve terminals, and imbalance causes neurodegenerative diseases of catecholamine systems. The second is that a buildup of catecholamines in the neuronal axoplasm leads to programmed cell death (apoptosis). In catecholaminergic cells we are testing the catecholaldehyde hypothesis. According to this hypothesis, catecholamines in the neuronal cytoplasm are converted to cytotoxic catecholaldehydes, via monoamine oxidase (MAO). In mouse pheochromocytoma cells (MPCs), which have a combined dopaminergic and noradrenergic phenotype, we have obtained preliminary evidence for apoptosis in cells exposed to reserpine, which blocks the vesiclar monoamine transporter and increases cytoplasmic catecholamine concentrations. Since PD is characterized by Lewy bodies, cytoplasmic inclusion bodies that contain aggregated alpha-synuclein, and since inherited alpha-synucleinopathies can cause familial PD, we are especially interested in interactions between catecholaldehydes and alpha-synuclein. We recently obtained preliminary evidence that the catecholaldehyde of DA, dihydroxyphenylacetaldehyde (DOPAL) oligomerizes alpha-synuclein, converting the normally soluble protein into a potentially pathogenic form. With the addition of Dr. Neptune Mizrahi, an experienced researcher in the area of development of catecholaminergic neurons in zebrafish, we plan on studying the development of noadrenergic innervation of the heart and interactions between manipulations of expression of genes or environmental exposures on the balance of neurotrophism and neurodegeneration in adult zebrafish, as a potential novel animal model of the central and peripheral catecholaminergic denervation characterizing PD. We will test the catecholaldehyde hypothesis, by examining whether in MPCs, MAO inhibition prevents reserpine-induced apoptosis, in a manner correlated with decreased catecholaldehyde production. With the addition of Dr. Nelson Cole, an experienced researcher in the area of alpha-synuclein, we will study about alpha-synuclein-catecholamine interactions in cellular and animal models, DOPAL is detoxified by aldehyde dehydrogenase (AD), and using liquid chromatography with tandem mass spectroscopy (LC/MS/MS), we hope to identify patients with PD who have decreased AD activity. Identification of abnormal catecholamine metabolic profiles should spur hypothesis-driven genomic, proteomic, and biopsy studies elucidating mechanisms of PD and related disorders.