Protein Disulfide Stress: Proposed Radical‐Free Bridges to Neurodegeneration

Oxidative crosslinking of protein thiols via disulfide bonds, promoted by non‐radical peroxides, offers alternatives to traditional, oxygen radical‐centered, perspectives with which to consider the impacts of oxidative stress on brain functions. Protein disulfides, involving the bridging of closely‐spaced (vicinal) thiol pairs, as well as protein‐glutathione mixed disulfides occur readily in cells exposed to hydrogen peroxide but the scope, pathways, and relationships to health and disease of protein thiol oxidations in the brain remain to be fully established. We demonstrated recently that (i) brains of healthy adolescent rats, from different sources, could be distinguished by ratios of oxidized to reduced glutathione and (ii) moderate increases in these ratios were associated with marked elevations in the levels of total protein disulfides but not mixed disulfides. We report here that the more oxidized brains were characterized also by increases in the protein levels of thioredoxin (Trx)‐dependent peroxiredoxin (Prx) peroxidases as well as the extents of oxidations of the catalytic vicinal thiols of these enzymes. Moreover, among the non‐Prx proteins that were oxidized most prominently were glyceraldehyde‐3‐phosphate dehydrogenase and the catalytic subunit(s) of the Na + , K + ‐ATPase, critical enzymatic determinants of glucose utilization and neuronal excitability, respectively. We hypothesize that radical‐free oxidations of protein vicinal thiol motifs, controlled by the Trx/Prx system, may facilitate short‐term adaptation to oxidative stress but that prolonged oxidations, i.e., protein disulfide stress, may derail healthy brain aging by increasing the vulnerability of neurons to excitotoxic insults.