We suggest that increased SOD1 expression can lead to tau hyperphosphorylation, which might serve as an important contributing factor to the etiology of Down syndrome and SOD1-related ALS disease.
The missense mutation of SOD1 gene in two of the three alleles could have increased its toxic effects in the Down syndrome patient leading to an earlier onset and rapid progression of the disease.
These results highlight DS as a model to understand the role of APOE4 allele in unsuccessful ageing considering that a number of proinflammatory supernumerary genes (Cu/Zn superoxide dismutase, Ets-2 transcription factors, Down syndrome critical region 1, stress-inducible factor, interferon-alpha receptor and the amyloid precursor protein) are located on chromosome 21 and are implied in the pathologic processes of DS.
Our findings suggest that genes on the trisomic Ts1Cje segment other than APP and SOD1 can cause oxidative stress, mitochondrial dysfunction and hyperphosphorylation of tau, all of which may play critical roles in the pathogenesis of mental retardation in DS.
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).
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.
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.
We have therefore investigated global gene expression profiles in Ts1Cje, a mouse model for DS that displays learning deficits and has a segmental trisomy of chromosome 16 orthologous to a segment of human chromosome 21 spanning from Sod1 to Znf295.
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.
They also show the potentially deleterious effects of SOD1 overexpression on cellular proliferation, which may be relevant to abnormal development in DS.
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.
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.
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.
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.
Mutations in the genes Minibrain and SOD1 have been implicated in the development of learning defects in Down syndrome and many new genes from human chromosome 21 are being cloned, which should result in the genesis of other models that phenocopy one or more pathologies of the syndrome.
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 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.