Redox proteomics analysis of 4-hydroxynonenal-modified proteins in brain from Down Syndrome

Down syndrome (DS) is the most common genetic cause of intellectual disability, due to partial or complete triplication of chromosome 21 (Chr21). DS subjects are characterized by a number of abnormalities including mental retardation, premature aging and development of Alzheimer’s-like dementia after 40 years. Several studies showed that oxidative stress play a crucial role in the development of neurodegeneration in DS. Increased lipid peroxidation is one of the main events causing redox imbalance within cells through the formation of toxic aldehydes that easily react with DNA, lipid and proteins. In this study we used a redox proteomics approach to identify specific target of 4-hydroxynonenal modification in the frontal cortex from DS (under the age of 40, DSyg) and DS-AD (over the age of 40) subjects compared with age-matched controls. Our results show that increased oxidation of specific protein occurs already in DS yg and further progress in DS/AD subjects. In particular, a group of these proteins follow a specific pattern of oxidation in DS yg vs CTR yg as characteristic features of DS phenotype; a second group show increased oxidation from DS yg to DS/AD, thus possibly playing a role in the development of AD-like dementia. Oxidized protein are involved in important biological functions including intracellular quality control system, energy metabolism and antioxidant response. In conclusion, our results show that oxidative damage is an early event in DS, as well as dysfunctions of protein degradation systems and cellular protective pathways, suggesting that DS subjects are more vulnerable to accumulate oxidative damage which might contribute to AD development.