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

Oxygen (O₂) sensing is the fundamental process through which organisms respond to changes in O₂ levels. Complex networks exist allowing the maintenance of O₂ levels through the perception, capture, binding, transport, and delivery of molecular O₂. The brain extreme sensitivity to O₂ 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 O₂ sensing in relation to Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Over the years, it has been clarified that most NDs share common pathways, a great number of which are in relation to O₂ imbalance. These include hypoxia, hyperoxia, reactive oxygen species production, metabolism of metals, protein misfolding, and neuroinflammation. There is still a gap in knowledge concerning how O₂ sensing plays a role in the above indicated neurodegenerations. Specifically, O₂ concentrations are perceived in body sites that are not limited to the brain, but primarily reside in other organs. Moreover, the mechanisms of O₂ sensing, gene expression, and signal transduction seem to correlate with neurodegeneration, but many aspects are mechanistically still unexplained. Future studies should focus on the precise characterization of O₂ level disruption and O₂ sensing mechanisms in NDs. Moreover, advances need to be made also concerning the techniques used to assess O₂ 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.