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
 
 
 
 
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