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.
| Imrich, Richard; Eldadah, Basil A; Bentho, Oladi et al. (2009) Functional effects of cardiac sympathetic denervation in neurogenic orthostatic hypotension. Parkinsonism Relat Disord 15:122-7 |
| Sharabi, Yehonatan; Imrich, Richard; Holmes, Courtney et al. (2008) Generalized and neurotransmitter-selective noradrenergic denervation in Parkinson's disease with orthostatic hypotension. Mov Disord 23:1725-32 |
| Goldstein, David S (2008) Genotype and vascular phenotype linked by catecholamine systems. Circulation 117:458-61 |
| Goldstein, David S; Holmes, Courtney (2008) Neuronal source of plasma dopamine. Clin Chem 54:1864-71 |
| Goldstein, David S; Holmes, Courtney; Bentho, Oladi et al. (2008) Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple system atrophy. Parkinsonism Relat Disord 14:600-7 |
| Kaler, Stephen G; Holmes, Courtney S; Goldstein, David S et al. (2008) Neonatal diagnosis and treatment of Menkes disease. N Engl J Med 358:605-14 |
| Moak, Jeffrey P; Goldstein, David S; Eldadah, Basil A et al. (2007) Supine low-frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation. Heart Rhythm 4:1523-9 |
| Goldstein, D S; Imrich, R; Peckham, E et al. (2007) Neurocirculatory and nigrostriatal abnormalities in Parkinson disease from LRRK2 mutation. Neurology 69:1580-4 |
| Goldstein, David S (2007) Cardiac denervation in patients with Parkinson disease. Cleve Clin J Med 74 Suppl 1:S91-4 |
| Goldstein, David S; Kopin, Irwin J (2007) Evolution of concepts of stress. Stress 10:109-20 |
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