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

Oxygen (O) sensing is the fundamental process through which organisms respond to changes in O levels. Complex networks exist allowing the maintenance of O levels through the perception, capture, binding, transport, and delivery of molecular O. The brain extreme sensitivity to O 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 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 O 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 O sensing plays a role in the above indicated neurodegenerations. Specifically, O concentrations are perceived in body sites that are not limited to the brain, but primarily reside in other organs. Moreover, the mechanisms of O 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 O level disruption and O sensing mechanisms in NDs. Moreover, advances need to be made also concerning the techniques used to assess O 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. 38, 160-182.