Oxygen Sensing in Neurodegenerative Diseases: Current Mechanisms, Implication of Transcriptional Response, and Pharmacological Modulation

Significance: Oxygen (O-2) sensing is the fundamental process through which organisms respond to changes in O-2 levels. Complex networks exist allowing the maintenance of O-2 levels through the perception, capture, binding, transport, and delivery of molecular O-2. The brain extreme sensitivity to O-2 balance makes the dysregulation of related processes crucial players in the pathogenesis of neurodegenerative diseases (NDs). In this study, we wish to review the most relevant advances in O-2 sensing in relation to Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.Recent Advances: Over the years, it has been clarified that most NDs share common pathways, a great number of which are in relation to O-2 imbalance. These include hypoxia, hyperoxia, reactive oxygen species production, metabolism of metals, protein misfolding, and neuroinflammation.Critical Issues: There is still a gap in knowledge concerning how O-2 sensing plays a role in the above indicated neurodegenerations. Specifically, O-2 concentrations are perceived in body sites that are not limited to the brain, but primarily reside in other organs. Moreover, the mechanisms of O-2 sensing, gene expression, and signal transduction seem to correlate with neurodegeneration, but many aspects are mechanistically still unexplained.Future Directions: Future studies should focus on the precise characterization of O-2 level disruption and O-2 sensing mechanisms in NDs. Moreover, advances need to be made also concerning the techniques used to assess O-2 sensing dysfunctions in these diseases. There is also the need to develop innovative therapies targeting this precise mechanism rather than its secondary effects, as early intervention is necessary. Antioxid. Redox Signal. 38, 160-182.