Free radical-mediated damage to proteins is particularly important in aging and age-related neurodegenerative diseases, because in the majority of cases it is a non-reversible phenomenon that requires clearance systems for removal. Major consequences of protein oxidation are loss of protein function and the formation of large protein aggregates, which are often toxic to cells if allowed to accumulate. Deposition of aggregated, misfolded, and oxidized proteins may also result from the impairment of protein quality control (PQC) system, including protein unfolded response, proteasome, and autophagy. Perturbations of such components of the proteostasis network that provides a critical protective role against stress conditions are emerging as relevant factor in triggering neuronal death. In this outlook paper, we discuss the role of protein oxidation as a major contributing factor for the impairment of the PQC regulating protein folding, surveillance, and degradation. Recent studies from our group and from others aim to better understand the link between Down syndrome and Alzheimer’s disease neuropathology. We propose oxidative stress and alteration of proteostasis network as a possible unifying mechanism triggering neurodegeneration. 1. Introduction Oxidative stress (OS) refers to a condition where reactive oxygen species (ROS) or other oxidants overwhelm the cellular antioxidant defense system, by an increase of ROS production and/or a decrease in the antioxidant response. ROS, such as superoxide anion ( ), hydrogen peroxide (H2O2), and hydroxyl radical ( ), are both radical and nonradical oxygen species formed by the partial reduction of oxygen. The major source of free radicals is the oxidative phosphorylation where electron leakage from the mitochondrial electron transport chain causes the formation of superoxide anion, or they can be released by exogenous sources such as xenobiotic compounds [1]. Oxidative stress damages all macromolecules (carbohydrates, nucleic acids, lipids, and proteins) and is implicated in the pathogenesis and progression of various diseases such as atherosclerosis, cancer, neurodegeneration, and aging as well. Indeed, the rate of generation of ROS in different species roughly correlates with life span and is a major contributor in defining the rate of aging and the development of age-related diseases [2]. The “oxidative stress theory” of aging, proposed by Harman [3], holds that a progressive and irreversible accumulation of oxidative damage impacts on critical aspects of the senescence process, contributing to impaired
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