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Dear PARKINSN friends, It is with interest that I followed the recent discussion on inheritance, genetic components, etc., in the etiology of PD. This may be old news to most of you - I'm still relatively new to the group. ;) Recent research results point towards interesting mechanisms (which may eventually prove to have a genetic basis) involved in the etiology of PD . The majority of recently published papers implicate a problem in the mitochondrial oxidative pathway of cells producing dopamine. The current state of knowledge in this regard was aptly summarized by Dr Schapira in Movement Disorders (see below). Attempts to calculate the heretibility of PD (with a few notable exceptions), or the specific effect of an environmental factor, may thus be somewhat premature, as the basic biochemical and molecular mechanisms remain unknown. To me, it basically appears impossible to separate the environmental factors from genetic factors if you do not know exactly what you are looking for (families tend to have the same eating habits or at least for some time stay in the same area). Kind regards, Hans. (PS. From published literature it presently does not appear that the lack of natural antioxidants (Vit E, Vit C) is implicated in, or connected to the precipitation (penetrance) of PD, although severe depletion under experimental conditions can produce Parkinsonian-like symtoms in experimental animals (in relation to free radicals/super oxides below)). Schapira, A.H.V. Evidence for Mitochondrial Dysfunction in Parkinsons Disease - A Critical Appraisal. Movement Disord 9:125-138, 1994. Abstract: There is now considerable evidence to support a defect of the mitochondrial respiratory chain, and complex I in particular, in Parkinson's Disease (PD). However, the site specificity of the defect within the chain, its anatomical selectivity within the brain, and its presence in other tissues still remain controversial. Much of the present confusion surrounding the mitochondrial defect can be dispelled by careful analysis of the available data. The molecular basis of the deficiency and its relevance to the pathogenesis of PD remain unknown. Nevertheless, the complex I deficiency in PD provides a direct biochemical link between the idiopathic disease and the MPTP toxin model. The relationship between the mitochondrial defect and other abnormalities within the PD substantia nigra suggests that a self amplifying cycle of events might be precipitated either by a genetic or environmentally induced abnormality of mitochondrial function or free radical metabolism. Alternatively, a biochemical event separate from these might precipitate a cascade which terminates in complex I dysfunction and free radical formation. An understanding of the molecular basis of the complex I defect in PD and its relationship to other biochemical changes will provide important insight into the potential chain of events that lead to dopaminergic cell death in PD. Poirier, J. and Thiffault, C. Are Free Radicals Involved in the Pathogenesis of Idiopathic Parkinson's Disease. Eur Neurol 33:38-43, 1993. Abstract : Since the original description of Parkinson's disease (PD) more than 170 years ago, there have been major advances in the understanding and treatment of PD. This article reviews some current knowledge concerning the role of free radicals, especially superoxide, in the etiology of PD. Hypotheses regarding inhibition of mitochondrial respiration and free radicals generation in PD are discussed in relation to the mechanisms of action of the N-methyl-4-phenyl-1,2,3,6- tetrahydropyridine, a neurotoxin known to produce parkinsonian syndromes. Other relevant publications (please eMail me -- [log in to unmask] -- directly if you require abstracts: Smith, P.R., Cooper, J.M., Govan, G.G., Harding, A.E. and Schapira, A.H.V. Smoking and Mitochondrial Function - A Model for Environmental Toxins. Q J Med 86:657-660, 1993. Dimauro, S. Mitochondrial Involvement in Parkinson's Disease - The Controversy Continues. Neurology 43:2170-2172, 1993. Cardellach, F., Marti, M.J., Fernandezsola, J., Marin, C., Hoek, J.B., Tolosa, E. and Urbanomarquez, A. Mitochondrial Respiratory Chain Activity in Skeletal Muscle from Patients with Parkinson's Disease. Neurology 43:2258-2262, 1993. Didonato, S., Zeviani, M., Giovannini, P., Savarese, N., Rimoldi, M., Mariotti, C., Girotti, F. and Caraceni, T. Respiratory Chain and Mitochondrial DNA in Muscle and Brain in Parkinson's Disease Patients. Neurology 43:2262-2268, 1993. Edwards, R.H. Neural Degeneration and the Transport of Neurotransmitters. Ann Neurol 34:638-645, 1993. Przedborski, S., Jacksonlewis, V., Muthane, U., Jiang, H., Ferreira, M., Naini, A.B. and Fahn, S. Chronic Levodopa Administration Alters Cerebral Mitochondrial Respiratory Chain Activity. Ann Neurol 34:715-723, 1993. Hartley, A., Cooper, J.M. and Schapira, A.H.V. Iron Induced Oxidative Stress and Mitochondrial Dysfunction -Relevance to Parkinson's Disease. Brain Res 627:349-353, 1993. Ceballospicot, I. Transgenic Mice Overexpressing Copper-Zinc Superoxide Dismutase as Models for the Study of Free Radicals Metabolism and Aging. C R Soc Biol 187:308-323, 1993. Turski, L. and Turski, W.A. Towards an Understanding of the Role of Glutamate in Neurodegenerative Disorders - Energy Metabolism and Neuropathology. Experientia 49:1064-1072, 1993. Temlett, J.A., Landsberg, J.P., Watt, F. and Grime, G.W. Increased Iron in the Substantia Nigra Compacta of the MPTP-Lesioned Hemiparkinsonian African Green Monkey - Evidence from Proton Microprobe Elemental Microanalysis. J Neurochem 62:134-146, 1994. Mizuno, Y., Mochizuki, H., Nishi, K., Ikebe, S.I., Hattori, N. and Hattorinakagawa, Y. Pathogenesis of Parkinson's Disease - Iron and Mitochondrial DNA Deletion. In: Iron in Central Nervous System Disorders, edited by Riederer, P. and Youdim, M.B.H. Springer-Verlag, 1993, p. 117-135. Benecke, R., Strumper, P. and Weiss, H. Electron Transfer Complexes I and IV of Platelets Are Abnormal in Parkinsons Disease But Normal in Parkinson- Plus Syndromes. Brain 116:1451-1463, 1993. Veitch, K. and Hue, L. Flunarizine and Cinnarizine Inhibit Mitochondrial Complexes I and II - Possible Implication for Parkinsonism. Mol Pharmacol 45:158-163, 1994. Dexter, D.T., Sian, J., Rose, S., Hindmarsh, J.G., Mann, V.M., Cooper, J.M., Wells, F.R., Daniel, S.E., Lees, A.J., Schapira, A.H.V., Jenner, P. and Marsen, C.D. Indices of Oxidative Stress and Mitochondrial Function in Individuals with Incidental Lewy Body Disease. Ann Neurol 35:38-44, 1994. Factor, S.A., Ortof, E., Dentinger, M.P., Mankes, R. and Barron, K.D. Platelet Morphology in Parkinsons Disease - An Electron Microscopic Study. J Neurol Sci 122:84-89, 1994. Mizuno, Y., Matuda, S., Yoshino, H., Mori, H., Hattori, N. and Ikebe, S. An Immunohistochemical Study on alpha-Ketoglutarate Dehydrogenase Complex in Parkinsons Disease. Ann Neurol 35:204-210, 1994. Jenner, P. Presymptomatic Detection of Parkinsons Disease. J Neural Transm-Gen Sect 23-36, 1993. Youdim, M.B.H. and Riederer, P. The Role of Iron in Senescence of Dopaminergic Neurons in Parkinsons Disease. J Neural Transm-Gen Sect 57-67, 1993. Dimonte, D.A., Sandy, M.S., Jewell, S.A., Adornato, B., Tanner, C.M. and Langston, J.W. Oxidative Phosphorylation by Intact Muscle Mitochondria in Parkinsons Disease. Neurodegeneration 2:275-281, 1993. Cobuzzi, R.J., Neafsey, E.J. and Collins, M.A. Differential Cytotoxicities of N-Methyl-beta-Carbolinium Analogues of MPP+ in PC12 Cells - Insights into Potential Neurotoxicants in Parkinsons Disease. J Neurochem 62:1503-1510, 1994. Lastly, two references dealing with inherited predisposition to PD: Kurth, M.C. and Kurth, J.H. Variant Cytochrome P450 CYP2D6 Allelic Frequencies in Parkinson's Disease. Am J Med Genet 48:166-168, 1993. Bhatia, K.P., Daniel, S.E. and Marsden, C.D. Familial Parkinsonism with Depression - A Clinicopathological Study. Ann Neurol 34:842-847, 1993. ===================================================================== Hans van Zyl | Cell Physiology Group | [log in to unmask] Irene Animal Production Institute | Tel: (27) 12 672 9261 Private Bag X2 | Fax: (27) 12 665 1604 IRENE 1675, South Africa | =====================================================================