Oxidative stress and neural dysfunction in Down Syndrome
Total or partial trisomy of chromosome 21 occurs with relatively high frequency and is responsible for the occurrence of Down syndrome. Phenotypically, individuals with Down syndrome display characteristic morphological features and a variety of clinical
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Summary. Total or partial trisomy of chromosome 21 occurs with relatively high frequency and is responsible for the occurrence of Down syndrome. Phenotypically, individuals with Down syndrome display characteristic morphological features and a variety of clinical disorders. One of the challenges for researchers in this field has been to ascertain and understand the relationship between the Down syndrome phenotype with the gene dosage effect resulting from trisomy of chromosome 21. Much attention therefore, has been given towards investigating the consequences of overexpressing chromosome 21-linked genes. In particular, an extensive analysis of SOD1 and APP have provided important insights as to how perturbations in the expression of their respective genes may contribute to the Down syndrome phenotype. 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. Central to this relationship is how the redox state of the cell is affected and its consequences to neural function and integrity.
Introduction
One of the most prevalent genetic disorders in our community today is Down syndrome (DS). It occurs at a frequency of one in 700-1,000 live births and results as a consequence of either a total or partial trisomy of chromosome 21 (Lejeune et aI., 1959). Although patients with DS are characterised by very specific morphological features (Patterson, 1987), they exhibit a broad and varied range of clinical pathologies including mental retardation, microcephaly, bone and skeletal abnormalities, congenital malformations, and increased incidence of leukemia and diabetes (Epstein, 1986; Pueschel, 1990; Kola, 1997; Kola and Hertzog, 1997). One of the most obvious features of DS is premature aging, with many DS individuals often developing an early onset of Alzheimer's type dementia (Kesslak et aI., 1994; Korenberg, 1995). A central approach towards elucidating the mechanisms which contribute to the different pathologies in DS is based on the favoured hypothesis that DS is a gene dosage disorder (Anneren and Edman, 1993; Groner, 1995; Sumarsono et aI., 1996; Kola, 1997). As such, considerable effort and progress
G. Lubec (ed.), The Molecular Biology of Down Syndrome © Springer-Verlag Wien 1999
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is being made towards the identification and determination of the biological roles of chromosome 21-linked genes, several of which have already provided insights into the molecular processes underlying this disorder (Kola and Hertzog, 1997). One of these processes implicates reactive oxygen species (ROS) as important contributors in the pathogenesis of the DS phenotype. ROS are molecules which are formed spontaneously as part of the natural cellular processes involving oxygen, and when present at relatively low concentrations, ROS serve as important signaling molecules and regulators of gene expression (Khan and Wilson, 1995; Winyard and Blake, 1997). However, at high concentrations, they have th
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