These results indicate that the Down syndrome phenotype of this patient is due to microduplication of a chromosome 21 fragment containing the CuZn SOD gene.
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.
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.
These animals provide a unique system for studying the consequences of increased dosage of the Cu/Zn-superoxide dismutase gene in Down syndrome and the role of this enzyme in a variety of other pathological processes.
These data are consistent with the possibility that gene dosage of superoxide dismutase 1 contributes to oxygen metabolism modifications previously described in Down's syndrome.
A speculative hypothesis about a gene dosage effect of Cu/Zn-superoxide dismutase in preventing toxic radical formation in the substantia nigra of DS patients is presented.
Cu,Zn superoxide dismutase (SOD-1) and glutathione peroxidase (GSHPx) activities were significantly elevated (1.39-fold and 1.24-fold, respectively) in DS individuals without AD.
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.
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.
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.
These results support the notion that CuZn SOD gene dosage effect could play a role in the pathogenesis of rapid aging features in the brain of Down's syndrome patients.
The erythrocyte superoxide dismutase-1 (SOD-1) was found to be normal, and so we conclude that SOD-1 excess is not necessarily observed in patients with Down's syndrome caused by partial 21 trisomy.
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.
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.
DRG neurons which possessed additional copies of the gene for human superoxide dismutase-1 (SOD), a gene from the Down syndrome region of chromosome 21, were compared to normal neurons.
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.
These findings suggest that CuZnSOD gene dosage is affecting the dense granule transport system and is thereby involved in the depressed level of blood serotonin found in patients born with Down's syndrome.
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 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.
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.