Theoretical Construct 1 1) Parkinson's Disease is actually a syndrome of symptoms resulting from impaired functioning of the dopaminergic neuronal pathways, and has multiple causes. 2) A subset of Parkinson's disease is caused by a retrovirus. Facts explained: a) Joe Burke's symptoms developed a few years after prolonged close association with a friend who had Parkinson's. b) Some anti-viral medications, e.g. Amantadine, also have some efficacy against Parkinson's disease. The mechanism of action is unclear. This was the only medication Joe tried that exerted a marked effect on his Parkinson's symptoms. c) Approximately 10% of patients with apparently idiopathic Parkinson's do not respond well to L-DOPA therapy. Joe and his friend both fell into this category. d) The progression of the disease, with short periods of marked deterioration followed by long periods of stable symptom pattern or slow improvement, but with an overall pattern of decline over several years, is consistent with the expected progression for retroviral infection. e) Microglial reactivity and activation seen in the substantia nigra of Parkinson's disease patients at time of death implies an immune reaction. (11) 3) The seborrheic dermatitis often associated with Parkinson's disease is a defense reaction by which the body limits the availability of myristic acid, a critical component of the retroviral virion. Facts explained: a) A critical step in the release of retroviral virions from an infected cell is the attachment of a myristic acid moiety to the amino end of the Gag precursor protein. (4) b) Myristic acid is a 14-carbon saturated fatty acid. Mammalian lipases construct fatty acids with at least 16 carbons. We get myristic acid in our diet and from comensal microbes including lipophilic Malassezia yeasts that inhabit the sebaceous regions of the skin.(1) c) Malassezia yeasts have been associated with seborrheic dermatitis, but in some indirect way. Treatment with antifungal agents is effective and the dermatitis returns when the yeast population builds back up. (10,9,5,6) But no consistent differences in yeast population have been shown between patients with and without seborrheic dermatitis, and one study comparing normal healthy subjects, patients with seborrheic dermatitis, and patients with other inflammatory syndromes, showed no significant difference in immune response to specific M. furfur proteins. The authors suggest the dermatitis is caused by a low molecular weight lipophilic product of the yeast.(9) d) Patients with seborrheic dermatitis have an increased irritant reaction to sodium lauryl sulfate, which can act as a substrate for microbial lipases.(5) e) Patients with HIV, a known retrovirus, tend to have severe seborrheic dermatitis. (5,9,8) 4) Some component of coffee, possibly other than caffeine, protects against retroviral Parkinson's disease by a direct mechanism. Facts explained: a) Several epidemiological studies indicate that coffee has a mild, but definite protective effect against Parkinson's. In a case-control study, there were fewer coffee drinkers among the patients with Parkinson's than among the control group, and age at onset of symptoms for those Parkinson's patients who were coffee drinkers was, on average, eight years later than for Parkinson's patients who were not coffee drinkers. (2) b) Consumption of other caffeine-containing items, such as tea and chocolate does not appear to provide this protective effect. 5) Mitochondrial dysfunction exacerbates Parkinson's Disease, whether retroviral or of other etiology. Facts explained: a) Deficiencies in mitochondrial electron transport have been demonstrated in Parkinson's patients. (7) b) Some patients with idiopathic Parkinson's have been shown to have a mutation in mitochondrial DNA that impairs the functioning of the electron transport chain. (3) Sources Aspiroz, C. et al., Differentiation of three biotypes of Malassezia species on human normal skin. Correspondence with M. globosa, M. sympodialis, and M. restricta. Mycopathologica 145:69-74. 1999. Benedetti, M. D., et al., Smoking, alcohol, and coffee consumption preceding Parkinson's disease: A case controlled study. Neurology 55:1350-58, 2000. Blake, B. et al., Biochemical Toxicology of the Central Nervous System, p 453-486 in Introduction to Biochemical Toxicology, 3rd ed, Hodgson, E. and Smart, R., eds. Wiley-Interscience, New York, 2001. Goff, S. P., Retroviridae: The Retroviruses and Their Replication, p 1871-1940 in Fields Virology 4th ed., Knipe, D. M. and Howley, P. M.,eds Lippincott, Williams, and Wilkins, Philadelphia,2001. Gupta, A. K. and Bluhm, R., Seborrheic dermatitis. J Eur Acad Dermatol Venereol 18:13. 2004. Gupta, A. K. and Plott, T., Ciclopirox: a broad-spectrum anti-fungal with anti-bacterial and anti-inflammatory properties. Int J Dermatol 43S:3-8. 2004. Hattori, N. et al., Importance of familial Parkinson's disease and parkinsonism to the understanding of nigral degeneration in sporadic Parkinson's disease p101-117 in Advances in Research on Neurodegeneration, Riederer, P. et al., eds, Springer-Verlag Wein. New York. 2000. Ostlere, LS et al., Skin surface lipids in HIV-positive patients with and without seborrheic dermatitis, Int J Dermatol 35:276-279. 1996. Parry, M. E. and Sharpe, G. R., Seborrhoeic dermatitis is not caused by an altered immune response to Malassezia yeast, Br J Dermatol 139:254-263. 1998. Scaparro, E. et al., Evaluation of the efficacy and tolerability of oral terbinafine (Daskil) in patients with seborrhoeic dermatitis. A multicentre, randomized, investigator-blinded, placebo-controlled trial. Br J Dermatol 144:854-7. 2001. Schapira, A. H. V., Mitochondrial Dysfunction and Oxidative Damage in Parkinson's Disease, p 343-359 in Mitochondria and Free Radicals in Neurodegenerative Diseases, Beal, M. F., et al. eds., Wiley-Liss, New York, 1997.