When safeguarding goes wrong: Impact of oxidative stress on protein homeostasis in health and neurodegenerative disorders

Cellular redox status is an established player in many different cellular functions. The buildup of oxidants within the cell is tightly regulated to maintain a balance between the positive and negative outcomes of cellular oxidants. Proteins are highly sensitive to oxidation, since modification can cause widespread unfolding and the formation of toxic aggregates. In response, cells have developed highly regulated systems that contribute to the maintenance of both the global redox status and protein homeostasis at large. Changes to these systems have been found to correlate with aging and age-related disorders, such as neurodegenerative pathologies. This raises intriguing questions as to the source of the imbalance in the redox and protein homeostasis systems, their interconnectivity, and their role in disease progression. Here we focus on the crosstalk between the redox and protein homeostasis systems in neurodegenerative diseases, specifically in Alzheimer's, Parkinson's, and ALS. We elaborate on some of the main players of the stress response systems, including the master regulators of oxidative stress and the heat shock response, Nrf2 and Hsf1, which are essential features of protein folding, and mediators of protein turnover. We illustrate the elegant mechanisms used by these components to provide an immediate response, including protein plasticity controlled by redox-sensing cysteines and the recruitment of naive proteins to the redox homeostasis array that act as chaperons in an ATP-independent manner.