Mechanisms of Parkinson Disease and Related Disorders

点击翻译按钮获取中文摘要

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.