%0 Journal Article
%T Oxidative Stress and Mitochondrial Dysfunction in Down¡¯s Syndrome: Relevance to Aging and Dementia
%A Pinar E. Coskun
%A Jorge Busciglio
%J Current Gerontology and Geriatrics Research
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/383170
%X Genome-wide gene deregulation and oxidative stress appear to be critical factors determining the high variability of phenotypes in Down¡¯s syndrome (DS). Even though individuals with trisomy 21 exhibit a higher survival rate compared to other aneuploidies, most of them die in utero or early during postnatal life. While the survivors are currently predicted to live past 60 years, they suffer higher incidence of age-related conditions including Alzheimer¡¯s disease (AD). This paper is centered on the mechanisms by which mitochondrial factors and oxidative stress may orchestrate an adaptive response directed to maintain basic cellular functions and survival in DS. In this context, the timing of therapeutic interventions should be carefully considered for the successful treatment of chronic disorders in the DS population. 1. Introduction Down¡¯s syndrome (DS) or trisomy 21 is a prevalent genetic cause of intellectual disability due to full or partial triplication of chromosome 21 (HSA21). The presentation varies greatly between individuals. The molecular bases of this variation is ¡°the gene dosage effect¡± caused by the extra chromosome 21, which leads to a global imbalance on gene expression [1]. However, the molecular mechanisms by which such gene dosage imbalance causes DS-specific abnormalities remain unclear. Albeit trisomy 21 is the most common aneuploidy that infants can survive, the rate of miscarriage of fetuses with DS during the first trimester is almost 50% [2]. The survival rate for the first 18 years of life of DS individuals is 50.3% of the total DS population, and the greatest percent of deaths is observed during the first 5 years of life (35.9%). The death rate drops to 13.1% between 19 and 40 years, and DS individuals of 40+ years have a greater chance to live beyond 60 years of age in developed countries, especially those without congenital heart disease [3]. A remarkable feature of the syndrome is the presence of Alzheimer¡¯s disease (AD) neuropathology in the brain of nearly all DS individuals, the majority of which develop dementia with age [4]. Besides dementia, other aging features appear prematurely such as cataracts, diabetes, hair graying, leukemia, and hearing and visual impairment. Together, they define DS as a ¡°segmental progeroid syndrome¡± [5¨C7]. Mitochondria represent both a principal source as well as a target of free radicals, which in turn cause structural damage and activate signaling pathways associated with ageing and age-related diseases [8¨C10]. Both oxidative stress and mitochondrial dysfunction are prominent features of
%U http://www.hindawi.com/journals/cggr/2012/383170/