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Judith: Zinc levels seem to be altered in the PD brain (ref 3). However, it is unclear at this stage whether this may be regarded as a cause or an effect of PD. Altered Zinc levels appear to follow oxidative stress (see ref 1), the importance of which is well established in the etiology of PD. The following references might be interesting: 1. Shiraga, H., Pfeiffer, R.F. and Ebadi, M. The Effects of 6-hydroxydopamine and Oxidative Stress on the Level of Brain Metallothionein. Neurochem Int 23:561-566, 1993. Abstract : Oxidative stress, resulting either from excess generation or reduced scavenging of free radicals, has been proposed to play a role in damaging striatal neurons in Parkinson's disease. Since metallothionein is able to regulate the intracellular redox potential, we have undertaken a group of experiments to see whether or not 6-hydroxydopamine, which generates free radicals and is toxic to dopaminergic neurons, could alter the level of zinc and metallothionein. 6-Hydroxydopamine (8 mug in 4 mul 0.02% ascorbic acid) reduced the level of zinc and metallothionein in the striatum but not other brain regions tested. Dopamine plus selegiline increased the synthesis of metallothionein in Chang cells as judged by enhanced incorporation of [S-35]cysteine into metallothionein. The effect of dopamine was selective, in that dopamine could not stimulate the synthesis of metallothionein in neuroblastoma IMR-32 cells, which are devoid of dopaminergic receptors. The effect of dopamine in stimulating the synthesis of metallothionein was similar to that of zinc, known to generate the synthesis of metallothionein, and to that of H2O2 and FeS04, known to generate free radicals. The results of these experiments provide additional evidence that zinc or zinc metallothionein are altered in conditions where oxidative stress has taken place. 2. 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. Abstract : Oxidants are ubiquitous in our aerobic environment and could play an etiological role in aging and neurodegenerative diseases such as Alzheimer's disease. All cells contain several antioxydant enzymes, most importantly, superoxide dismutases (MnSOD and CuZnSOD), glutathione peroxydase (GSH-Px), glutathione reductase and catalase. The individual contribution of these antioxidant enzymes in neuronal protection during aging and under in vivo conditions remains unknown. We feel that the use of genetic manipulations to construct cells and/or transgenic mice that specifically overexpress or lack a single function represent a way to an understanding of the role of the individual antioxidant enzymes in neuronal aging. Copper-zinc superoxide dismutase (CuZnSOD) is one of the genes encoded by chromosome 21. As a consequence of gene dosage excess, CuZnSOD activity and protein are increased by 50 % in all tissues of Down syndrome (DS) patients. It has been suggested that this increment, by accelerating hydrogen peroxide formation, might promote oxidative damage within DS cells and might be involved in the various neurobiological abnormalities found in DS such as premature aging and Alzheimer-type neurological lesions. Moreover, the level of CuZnSOD protein and mRNA is particularly high in pyramidal hippocampal neurons susceptible to degenerative processes in Alzheimer's disease, and in dopaminergic melanized-neurons vulnerable in Parkinson's disease. In order to test this hypothesis, we have created transfected cells and transgenic mice which express human CuZnSOD gene. An oversupply of this enzyme is not beneficial to the brain of transgenic mice and causes increased thiobarbituric-reactive substances (TBARS), an index of lipid peroxidation, and may be due to peroxides generated by an imbalance between enzymatic activities of CuZnSOD and GSH-Px. Unlike what has been observed in transfected cells with the human CuZnSOD gene, but similar to what was found in the DS fetal brain, the GSH- Px activity was not increased in the brain of transgenic mice. One possibility to explain this discrepancy could be the differential cellular localization of these two enzymes in the brain (CuZnSOD in neurons and GSH-Px in glial cells). This heterogeneous cellular distribution of the enzymes implicated in oxygen-free radicals detoxification could participate to a selective neuronal degeneration. Interestlingly, overexpression of cuZnSOD in the brain of transgenic mice is associated with an increased MnSOD activity, the mitochondrial form of the enzyme. This increased MnSOD might be a defense response to protect mitochondria from oxidative damage. Alternatively, this MnSOD increase could lead to enhanced production of hydrogen peroxide inside the mitochondria leading to peroxidative damage and possibly to alterations of the mitochondrial genome, this latter appears to be more vulnerable to mutagenesis than the nuclear genome since it is not protected by histones or by competent repair mechanisms. Immunohistochemical and in situ hybridization analysis of brain sections reveals that human CuZnSOD protein and mRNA were preferentially expressed in neurons, particularly in the stratum pyramidale of Ammon's horn thoughout the CA1-CA4 fields of the hippocampus and in the granule cell layer of the dentate gyrus. Since expression of endogeneous CuZnSOD gene and human CuZnSOD gene is present in the age-vulnerable neurons of transgenic mice, we can now investigate whether there is a connection between the cell-specific overexpression, an accelerated aging, a neuronal pathology and mithochondrial damages by extended biochemical and neuroanatomical studies of the brain of transgenic mice, specially with regard to DS and Alzheimer-like neuropathology. 3. Yasui, M., Ota, K. and Garruto, R.M. Concentrations of Zinc and Iron in the Brains of Guamanian Patients with Amyotrophic Lateral Sclerosis and Parkinsonism Dementia. Neurotoxicology 14:445-450, 1993. Abstract : Simultaneous measurements of zinc (Zn) and iron (Fe) concentrations were determined using neutron activation analysis in gray and white matter of the frontal and occipital regions obtained from four patients with parkinsonism-dementia (PD), eight with amyotrophic lateral sclerosis (ALS), and four neurologically normal controls from Guam. Zn content in gray matter from the frontal cortex in ALS and PD cases was significantly decreased, compared with that of controls (p<0.05). No significant differences were found in the Zn content of white matter from the frontal cortex, and/or gray and white matter from the occipital cortex between the groups. The Zn content in gray matter from both frontal and occipital regions was less in ALS and PD patients than in controls. Fe content in gray matter from the frontal cortex of ALS and PD increased significantly compared with that of controls (p<0.05). Fe content in white matter from the frontal cortex in PD patients wa s greater than in controls (p<0.05), with a n overall difference: controls < ALS < PD. These data indicate that an increase in Fe in gray and white matter, and a decrease concentration of Zn in gray matter combined with an excess and deficiency of bioavailable aluminum and calcium, respectively, may be involved in the pathogenic process of these disorders. 4. 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. Abstract : Brain tissue from normal individuals with incidental Lewy bodies and cell loss in pigmented substantia nigra neurons (asymptomatic Parkinson's disease) and age-matched control subjects without nigral Lewy bodies was examined biochemically. There was no difference in dopamine levels or dopamine turnover in the caudate and putamen of individuals with incidental Lewy body disease compared to control subjects. There were no differences in levels of iron, copper, manganese, or zinc in the substantia nigra or other brain regions from the individuals with incidental Lewy body disease compared to those from control subjects. Similarly, ferritin levels in the substantia nigra and other brain areas were unaltered. There was no difference in the activity of succinate cytochrome c reductase (complexes II and III) or cytochrome oxidase (complex IV) between incidental Lewy body subjects and control subjects. Rotenonesensitive NADH coenzyme Q(1) reductase activity (complex I) was reduced to levels intermediate between those in control subjects and those in patients with overt Parkinson's disease, but this change did not reach statistical significance. The levels of reduced glutathione in substantia nigra were reduced by 35% in patients with incidental Lewy body disease compared to control subjects. Reduced glutathione levels in other brain regions were unaffected and there were no changes in oxidized glutathione levels in any brain region. Altered iron metabolism is not detectable in the early stages of nigral dopamine cell degeneration. There may be some impairment of mitochondrial complex I activity in the substantia nigra in Parkinson's disease. The marked reduction in nigral reduced glutathione levels suggests this to be an important early change in the process of oxidative stress underlying Parkinson's disease. Journal articles which mentions both OPCA and Parkinsonism are few and far between. Maybe Robert Fink could comment on the olivopontocerebellar atrophy-associated Parkinsonism mentioned below! Takada, M. and Kono, T. 3-Acetylpyridine Neurotoxicity to the Nigrostriatal Dopamine System in Mice. Neurosci Lett 161:211-214, 1993. Abstract : Employing tyrosine hydroxylase (TH) immunohistochemistry, the neurotoxic effects of 3-acetylpyridine (3-AP), a potent neurotoxin selective to olivocerebellar climbing fibers, on the mesencephalic dopamine systems were investigated in mice. Systemic injections of 3-AP resulted in a large loss of TH- immunoreactive nigrostriatal neurons. On the other hand, 3-AP neurotoxicity to the mesolimbic dopamine system was much less drastic. The 3-AP-induced concurrent loss of olivocerebellar and nigrostriatal neurons may replicate an essential neuropathological feature of olivopontocerebellar atrophy-associated parkinsonism. Hans ===================================================================== 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 | =====================================================================