Oxygen sensing in neurodegenerative diseases: current mechanisms, implication of transcriptional response and pharmacological modulation

Significance: Oxygen sensing is the fundamental process through which organisms respond to changes in oxygen levels. Complex networks exist allowing the maintenance of oxygen levels through the perception, capture, binding, transport and delivery of molecular oxygen. The brain extreme sensitivity to oxygen balance makes the dysregulation of related processes crucial players in the pathogenesis of neurodegenerative diseases. Here we wish to review the most relevant advances in oxygen 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 neurodegenerative diseases share common pathways, a great number of which are in relation to oxygen imbalance. These include hypoxia, hyperoxia, ROS production, metabolism of metals, protein misfolding and neuroinflammation. Critical Issues: There is still a gap in knowledge concerning how oxygen sensing plays a role in the above indicated neurodegenerations. Specifically, oxygen concentrations are perceived in body sites which are not limited to the brain, but primarily reside in other organs. Moreover, the mechanisms of oxygen 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 oxygen levels disruption and oxygen sensing mechanisms in neurodegenerative diseases. Moreover, advances need to be made also concerning the techniques used to assess oxygen 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.