Figure 11 Oxygen metabolism and possible abnormalities in ageing and disease.

Transgenic mice that over-express SOD1 also develop features of motor neurone disease after exposure to elevated levels of peroxide (50). The SOD1 gene is mutated in familial cases of motor neurone disease and the mutation is thought to produce a gain-of-function in that it appears that the H₂0₂ generated has the additional ability to oxidise other substrates such as SOD1 itself. Transgenic mice overexpressing a mutant form of SOD1 develop features of motor neurone disease, thus proving that this mutation is aetiological in the genesis of this disease (51). There have been no reports in the literature that indicate that individuals with Down syndrome develop motor neurone-like disease and the over-expression data emanating from the transgenic mice suggest that at least SOD1 over-expression predisposes to the development of motor neurone disease and that other oxidative stress is required to elicit mild forms of motor neurone disease.

There have also been some reports that implicate elevated levels of H₂0₂ in mediating the toxicity of the amyloid protein. Cells treated with the [beta]-amyloid protein display toxicities that are reversible by N-acetylcysteine and vitamin E, thus implicating H₂0₂ as the mediator of these toxicities (52). If such a situation was correct, then it could be exacerbated since oxidative stress can activate gene transcription via the heat shock element (53) and the APP gene promoter is known to contain a functional HSE (54); this in turn could result in elevated levels of APP and [beta] amyloid leading to further elevated H₂0₂ and the cascade could continue. However, these experiments need to be carried out in vivo via transgenic mice. In general, transgenic mice over-expressing APP or related peptides show some but not all of the features of Alzheimer's disease (55,56).

CONCLUSIONS

Gene knockout studies in mice are increasingly being employed to identify the function of genes on human chromosome 21 and thus far important data have been derived from such studies. These studies have the potential to illuminate the possible mechanisms involved in diseases/disorders that map to human chromosome 21; for example, the role of CBFA2 (AML1) in the genesis of haematopoietic lineages suggests that deregulation of the expression of this gene can result in the abnormalities in lineage development of haematopoietic cells that occur in leukaemias associated with translocations of this gene. However, only a few of the genes on human chromosome 21 have been knocked out. The genesis of other gene knockouts will illustrate the value/utility of these studies in illuminating the relationship of genes on human chromosome 21 with pathophysiologies associated with this chromosome.

Gene `knock in' studies in mice have thus far only been developed for limited studies on genes located on human chromosome 21. However, this is a powerful approach that will become more widely used to create mouse models of human disease, especially those that arise out of single gene mutations and/or the formation of chimaeric fusion transcripts resulting from chromosomal translocations. Further, this approach will be increasingly employed to `humanise' the mouse system.

Various approaches have been used to study the consequences of increased gene dosage in Down syndrome and particularly investigate phenotype/genotype relationships of genes. Also, many of these have been used to model Down syndrome. Thus far, no mouse exists that exactly models Down syndrome. However, many lines of mice exist that model one or more aspects/features of Down syndrome. The greatest value that has been derived from these studies has been the identification of genes related to specific phenotypic or pathophysiological features that occur in Down syndrome. Further, powerful insights into biochemical mechanisms operational in the genesis of these features have been derived. Importantly, many of these findings will have more widespread relevance since many of the individual parts that constitute the Down syndrome phenotype also occur in the general population. Thus, these types of studies may identify gene targets for drug therapy of these individual pathologies in the general population and the animal models generated may prove useful in the validation of such targets.

ACKNOWLEDGEMENTS

We are indebted to our colleagues in the Molecular Genetics and Development laboratory for generating some of the data presented in this review and for continual discussion of the concepts mentioned. We also acknowledge the National Health and Medical Research Council for grant support.

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*To whom correspondence should be addressed. Tel: +61 3 9550 5480; Fax: +61 3 9550 5568; Email: ismailko@silas.cc.monash.edu.au

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