Reactive Oxygen Species and Their Contribution to Pathology in Down Syndrome

Abstract

In addition to mental retardation, individuals with Down syndrome suffer from congenital heart defects, in utero growth retardation, increased susceptibility to infection; and a higher incidence of leukemia. These individuals show abnormalities of the viscerocranium those result in the characteristic facial features of Down syndrome; and features of premature aging. All individuals develop Alzheimer-type neuronal pathology. The involvement of reactive oxygen species (ROS) in some of the Down syndrome pathologies was initiated after assignment of the gene coding for Cu/Zn-superoxide dismutase (also known as Sodl) to chromosome21 in humans. All individuals with Down syndrome are either trisomic for the entire chromosome or part thereof. Increased gene dosage for Sodl has been proposed to contribute to the premature aging and/or mental retardation that occur as part of the syndrome. In gaining an understanding of how elevated Sodl levels may contribute to various pathologies in Down syndrome, this chapter delineates the physiological role for Sodl within cells. Elevated Sodl activity in Down syndrome could result in the accumulation of H202, which through the Fenton reaction could lead to a loss of cellular function through damage to macromolecules. The chapter discusses in detail the Sodl and Gpx1 expression levels in Down syndrome, premature aging of Down syndrome individuals, and apoptosis related to Down syndrome—some of the neurodegenerative symptoms and thymic destruction in Down syndrome may be because of the oxidative stress caused by the imbalance in the Sod/Gpx1 ratio, which in turn triggers apoptosis directly or confers an increased susceptibility of cells to apoptotic stimuli. Down syndrome is a situation where the antioxidant balance is affected because of gene dosage. Damage to biologically important macromolecules resulted because of the inability to prevent oxidative interactions. This accumulated macromolecular damage may be responsible for the abnormalities that are seen as part of the syndrome.