Catecholamine Autotoxicity: A Novel Experimental Therapeutic Target As explained in recent reviews (Goldstein, Cell Molec Neurobiol 2012;32:661-666;Goldstein, Comp Physiol, in press), scientific integrative medicine is a way of thinking that links systems biology with integrative physiology and pathophysiology. Concepts of scientific integrative medicine include negative feedback regulation, maintaining stability of the body's monitored variables; multiple effectors, enabling compensatory activation of alternative effectors and primitive specificity of stress response patterns; stress, applying a definition as a state rather than as an environmental stimulus or stereotyped response; and allostatic load, explaining chronic degenerative diseases in terms of effects of cumulative wear and tear. From computer models depicting these concepts graphically one can predict effects of stress and allostatic load on the transition from wellness to symptomatic disease. We applied these models to show how the above concepts may relate to novel treatment and prevention strategies for Parkinson disease (PD) and related disorders (Goldstein, Comp Physiol, in press). Cytosolic catecholamines are autotoxic, in that they undergo spontaneous oxidation to quinones and enzymatic oxidation to catecholaldehydes and hydrogen peroxide. According to the catecholaldehyde hypothesis, 3,4-dihydroxyphenylacetaldehyde (DOPAL), the immediate product of enzymatic oxidation of cytosolic dopamine by monoamine oxidase (MAO), kills catecholamine neurons, by cross-linking proteins, increasing formation of quinones and hydroxyl radicals, and oligomerizing and precipitating alpha-synuclein. We have proposed that DOPAL is a focal point in the induction of multiple, lethal, rapidly developing, largely irreversible positive feedback loops that cause the loss of catecholaminergic neurons in PD. The catecholaldehyde hypothesis predicts that MAO inhibition, aldehyde scavenging, increasing the efficiency of the type 2 vesicular monoamine transporter (VMAT2), increasing aldehyde dehydrogenase (ALDH) activity, and decreasing the production or effects of reactive oxygen species should attenuate or prevent death of catecholamine neurons. We have carried out initial experiments to test these predictions. In PC12 cells, apoptosis evoked by dopamine was found to result partly from increased DOPAL production, and MAO inhibition by pargyline prevented DOPA-induced dimerization of alpha-synuclein (Goldstein et al., J Neurochem 2012;123:932-943). In collaboration with R. Strong (Univ. of Texas) and M. Wey (Harvard), we obtained evidence that hydralazine treatment to scavenge aldehydes exerts neuroprotective effects in mice with double knockout of the ALDH1A1 and 2 genes (unpublished observations). In collaboration with G. Miller (Emory) we found that mice with very low VMAT2 activity have neurochemical evidence for high ALDH activity (Goldstein et al., J Neurochem 2013;126:591-603), possibly because of differential survival of animals able to detoxify DOPAL. By applying the concept of compensatory activation (Goldstein, Comp Physiol (in press)), one might optimize the timing for initiation of these treatments. As catecholamine stores become depleted, compensatory adjustments maintain dopaminergic function until the disease process in PD is far advanced. Ideal timing for initiation of treatment would be when the velocity of compensatory activation has peaked. Precursor Therapy for Norepinephrine Deficiency: Many studies using diverse methodologies have supported the view that PD involves loss not only loss of central dopaminergic but also loss of central noradrenergic neurons. We found that PD patients have decreased CSF and putamen tissue levels not only of 3,4-dihydroxyphenyacetic acid (DOPAC, the main neuronal metabolite of dopamine) but also of 3,4-dihydroxyphenylglycol (DHPG, the main neuronal metabolite of norepinephrine (NE), Goldstein et al., Brain 2012 135:1900-1913; Goldstein et al., Eur J Neurol 2011;18:703-710). We also found that mice with very low activity of the type 2 vesicular monoamine transporter have aging related loss of noradrenergic neurons of the locus ceruleus, the main source of NE in the brain (Taylor et al., in press). A vesicular-deamination shift would produce neurochemical changes similar to but not identical with functional dopamine-beta-hydroxylase (DBH) deficiency. Menkes disease is an X-linked recessive disorder of a copper ATP-ase. Since DBH is a copper enzyme, the disease features a buildup of DA and its deaminated metabolites relative to NE and its deaminated metabolites. Although both copper ATPase deficiency and a vesicular-deamination shift produce elevated DA:NE and DOPAC:NE ratios (Haddad et al., Mol Gen Metab 2012;107:222-228), and treatment with a precursor NE precursor bypasses the functional DBH deficiency (Donsante et al., Ann Neurol 2013;73:259-265), such treatment would not be expected to attenuate DOPAL formation. If studies that are in progress confirm an association between non-motor manifestations of PD and central NE deficiency (Jain &Goldstein, Neurobiol Dis 2012;46:505-507), then NE precursor therapy might prove beneficial. L-threo-dihydroxyphenylserine (L-DOPS) is undergoing clinical trials for treating orthostatic hypotension, which occurs in a substantial minority of PD patients. This drug might also increase NE production in the central nervous system and improve symptoms or signs of central NE deficiency. A theoretical limitation is neurotoxicity due to increased formation of 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), the catecholaldehyde produced from oxidative deamination of NE. Because the deuterium isotope effect stabilizes the alpha carbon-nitrogen bond of catecholamines such as NE, deuterated L-DOPS would be expected to be more potent and less toxic than non-deuterated L-DOPS. We have developed assay methodology for measuring DOPEGAL and found that deuterated NE is indeed less susceptible than non-deuterated NE to conversion to DOPEGAL. Targeting Neurocirculatory Abnormalities to Slow Cognitive Deterioration: Patients with PD often have orthostatic hypotension (OH) coupled with supine hypertension (SH). This combination can be found even in early, untreated PD, associated with white matter hyperintensities and cognitive dysfunction (Kim et al. Neurology 2012;79:1323-1331). Developing effective treatments for these neurocirculatory abnormalities is a novel approach to retard or prevent dementia in PD. OH+SH poses a difficult therapeutic challenge, because drug treatments to ameliorate symptoms of OH worsen SH. As a first step toward development of a prosthetic baroreceptor system to maintain blood pressure during orthostasis without worsening SH, we found that i.v. NE infusion temporarily eliminates OH (Goldstein et al., Clin Auton Res 2012;22:303-306). Further development of a prosthetic baroreceptor system would require validation of non-invasive means to track systemic hemodynamics accurately during activities of daily life. We recently compared three non-invasive means to track total peripheral resistance, a key systemic hemodynamic dependent measure. A commercially available gas re-breathing method yielded erroneous results, due to hemodynamic effects of the re-breathing maneuver itself (Sims-ONeil et al., unpublished observations). A less invasive alternative would be to develop an automated abdominal binder, to prevent orthostatic blood pooling and maintain venous return to the heart and thereby maintain blood pressure during orthostasis. Such a binder is under consideration by the Autonomic Rare Diseases Clinical Research Consortium.

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Haddad, Marie Reine; Choi, Eun-Young; Zerfas, Patricia M et al. (2018) Cerebrospinal Fluid-Directed rAAV9-rsATP7A Plus Subcutaneous Copper Histidinate Advance Survival and Outcomes in a Menkes Disease Mouse Model. Mol Ther Methods Clin Dev 10:165-178
Goldstein, David S; Holmes, Courtney; Cherup, Jamie et al. (2018) Plasma Catechols After Eating Olives. Clin Transl Sci 11:32-37
Goldstein, David S; Holmes, Courtney; Lopez, Grisel J et al. (2018) Cerebrospinal fluid biomarkers of central dopamine deficiency predict Parkinson's disease. Parkinsonism Relat Disord 50:108-112
Goldstein, David S; Holmes, Courtney; Lopez, Grisel J et al. (2018) Cardiac sympathetic denervation predicts PD in at-risk individuals. Parkinsonism Relat Disord 52:90-93
Goldstein, David S; Sharabi, Yehonatan (2017) The heart of PD: Lewy body diseases as neurocardiologic disorders. Brain Res :
Goldstein, David S; Jinsmaa, Yunden; Sullivan, Patti et al. (2017) N-Acetylcysteine Prevents the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PC12 Cells. Neurochem Res 42:3289-3295
Kaufmann, Horacio; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto et al. (2017) Natural history of pure autonomic failure: A United States prospective cohort. Ann Neurol 81:287-297
Goldstein, David S; Jinsmaa, Yunden; Sullivan, Patti et al. (2016) 3,4-Dihydroxyphenylethanol (Hydroxytyrosol) Mitigates the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PC12 Cells. Neurochem Res 41:2173-8
Aflaki, Elma; Borger, Daniel K; Moaven, Nima et al. (2016) A New Glucocerebrosidase Chaperone Reduces ?-Synuclein and Glycolipid Levels in iPSC-Derived Dopaminergic Neurons from Patients with Gaucher Disease and Parkinsonism. J Neurosci 36:7441-52
Goldstein, David S; Jinsmaa, Yunden; Sullivan, Patti et al. (2016) Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells. J Pharmacol Exp Ther 356:483-92

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