Redox Proteomics to Decipher the Neurobiology of Alzheimer Disease

Accumulation of oxidative damage is a common feature of neurodegeneration that together with mitochondrial dysfunction point to the fact that reactive oxygen species are a major attempt for neuronal homeostasis and survival. Among several targets of oxidative stress, free radical-mediated damage to proteins is particularly important in aging and age-related neurodegenerative diseases, because in the majority of cases it causes non-reversible modifications of protein structure likely leading to impaired activity. Redox proteomics studies are powerful tools to unravel the complexity of neurodegeneration, by allowing to identifying oxidative post-translational modifications that are proved to be detrimental for protein function. In particular we focus attention on specific pathways that underlie a shared deregulated scenario in both Down syndrome (DS) and Alzheimer neurodegeneration. Since after a critical age DS neuropathology shows similarities with Alzheimer disease, identification of common oxidized proteins by redox proteomics will help to understand the overlapping mechanisms that lead from normal aging to development of dementia. The most relevant proteomics findings highlight that dysfunction of specific members of the protein quality control, regulating protein folding, surveillance and degradation is caused by oxidative damage. Further, other major targets of oxidative damage are key metabolic enzymes that crucially regulate intracellular ATP levels. It is likely that “stressed” neurons have to challenge the increasing load of oxidatively modified proteins, which overwhelm the ability of protein quality control. This in turn further promotes the accumulation of damaged/misfolded proteins, increasingly prone to aggregation, ultimately resulting in neuronal death. Collectively, our results suggest that redox alteration of protein homeostasis coupled with increasing demand for protein degradation and reduced ATP production may promote a vicious cycle that push the neurodegenerative process.