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
 
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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.
 
 
 
 
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