Mechanisms of Parkinson Disease and Related Disorders

临床神经心脏病科（CNCS）关于帕金森病（PD）及相关疾病机制的研究主要有两种假说。首先，儿茶酚胺能神经支配反映了神经末梢萌发和丧失之间的平衡，不平衡导致儿茶酚胺系统的神经退行性疾病。二是神经元轴质中儿茶酚胺的积累导致程序性细胞死亡（细胞凋亡）。在儿茶酚胺能细胞中，我们正在测试儿茶酚醛假说。根据这一假说，神经元细胞质中的儿茶酚胺通过单胺氧化酶（MAO）转化为细胞毒性儿茶酚醛。小鼠嗜铬细胞瘤细胞（MPCs）具有多巴胺能和去甲肾上腺素能联合表型，我们已经获得了暴露于利血平的细胞凋亡的初步证据，利血平可以阻断囊泡单胺转运体并增加细胞质儿茶酚胺浓度。由于PD以含有聚集的α -突触核蛋白的路易小体为特征，并且由于遗传性α -突触核蛋白病可导致家族性PD，因此我们对儿茶酚醛和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的儿茶酚醛，二羟基苯乙醛（DOPAL）寡聚α -突触核蛋白，将正常可溶性蛋白转化为潜在的致病形式。

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.