CNS peroxiredoxins and their regulation in health and disease

Oxidative stress is thought to be a contributing factor in many chronic neurodegenerative pathologies, as well as acute cerebrovascular disorders such as stroke. Peroxiredoxins are a family of antioxidant enzymes that reduce peroxides directly through the use of a redox active cysteine within their active site, which in the process becomes oxidized. In order to cycle back to the reduced state, many peroxiredoxins rely on thiol-dependent reduction by the ubiquitous antioxidant enzyme thioredoxin. Peroxiredoxins, together with thioredoxin and thioredoxin's own 'recycling enzyme', thioredoxin reductase, represent an antioxidant enzymic system of growing significance in the context of neuronal physiology and pathology. Overexpression, knockdown, and knockout approaches have demonstrated an important role for peroxiredoxins in protecting neurons from oxidative insults. It is also becoming clear that neuronal peroxiredoxins are subjected to post-translational modifications that impair function as part of disease pathology. Conversely, components of this pathway are also subject to dynamic upregulation such as via endogenous synaptic activity-dependent signaling and induction of the Nrf2-dependent Phase II response. As such, the thioredoxin-peroxiredoxin system represents a potential therapeutic target for central nervous system disorders associated with oxidative stress.