It has been suggested that overexpression of copper-zinc superoxide dismutase (SOD-1) in DS may be involved in some of the abnormalities observed, mainly neurodegenerative and immunopathological processes.
Because both IfRec and SOD-1 map to mouse chromosome 16, it will now be possible to use mice trisomic for this chromosome to determine whether certain aspects of the Down syndrome phenotype in man are caused by an altered dosage of IfRec and SOD-1.
In this review we will highlight studies which support a key role for SOD1 and APP in the pathogenesis of neural abnormalities observed in individuals with Down syndrome.
In this regard, beta amyloid precursor protein (APP), CuZn superoxide dismutase (SOD1) and S100beta have been implicated in causing apoptosis, a mechanism thought to be responsible for neuronal loss in DS, in one way or another.
These transgenic mice provide an interesting model to investigate the deleterious effect of increased dosage of some chromosome 21 genes such as SOD-1 in the pathogenesis of DS.
The gene locus for human cytoplasmic superoxide dismutase (SOD-1; superoxide:superoxide oxidoreductase, EC 1.15.1.1) is located in or near a region of chromosome 21 known to be involved in Down syndrome.
Down's syndrome (trisomy 21) brain tissue is considered to be susceptible to oxidative injury, mainly because its increased Cu/Zn-superoxide dismutase (SOD1) activity is not followed by an adaptive rise in hydrogen peroxide metabolizing enzymes.
The results demonstrate that the enhancement in the level of mRNAs encoding SOD1 in DS male and female, as well as aged male and female are 51, 21, 31 and 50% respectively compared to the normal child (control).
The location of CBR near SOD1 and the increased enzyme activity and potential for free radical modulation in trisomy 21 cells implicate CBR as a candidate for contributing to the pathology of certain diseases such as Down syndrome and Alzheimer disease.
No detectable change was found in expression of SOD-1, catalase, phospholipid hydroperoxide glutathione peroxidase, glutathione reductase, antioxidant enzyme AOE372, thioredoxin-like protein and selenium binding protein between control and DS fetuses.
This suggests that the decreased expression of PRDX2 may contribute to the altered redox state in DS at levels comparable to that of the increased expression of SOD1.
Increased SOD-1 levels in patients with DS may reflect the overexpression by the trisomic state, as a response to the oxidative stress, as has been proposed in DS by several authors.
They also show the potentially deleterious effects of SOD1 overexpression on cellular proliferation, which may be relevant to abnormal development in DS.
Transgenic mice overexpressing the human copper/zinc superoxide dismutase (SOD1) gene are one of the first murine models for DS and it has been shown that SOD1 overexpression might be either deleterious or beneficial.
A child with characteristic clinical features of Down's syndrome and raised red cell SOD-1 activity was found to have, in addition to a single chromosome 21, a reverse dicentric tandem translocation of two No 21s with dual NORs and C band regions.
One of these, a girl trisomic for both segment 9pter to 9p24 and segment 21pter to 21q214, was found to have a SOD-A activity not significantly different from those found in a group of five cases with trisomy 21.