Exploring the role of HIF-1α in pathogenesis of parkinson's disease and its potential as a therapeutic target.

Hypoxia is an inadequate oxygen supply to the tissues, which hinders the brain's ability to produce energy and causes unconsciousness, followed by death in a matter of minutes. Upon detecting oxygen deprivation, the body initiates a cardiorespiratory response that includes increased lung ventilation, vasoconstriction, and an increased heart rate to improve oxygen supply. Moreover, during hypoxia, there is stabilization of hypoxia inducible factor (HIF), including HIF-1α and HIF-2α, where HIF-1α predominantly regulates genes involved in metabolic reprogramming and immediate stress response, and HIF-2α is engaged in sustaining vascular endothelial growth factor (VEGF) and erythropoietin (EPO) gene expression. The brain is an extremely oxygen-dependent organ, as it uses one-fifth of the body's oxygen at rest, making it particularly vulnerable during hypoxia. According to the literature, it results in metabolic changes in neurons via impacting various enzymatic activities, which further trigger inflammatory responses and oxidative stress, resulting in Parkinson's disease (PD). PD is a progressive neurodegenerative disease, characterised by α-synuclein aggregation, Lewy body formation, and dopaminergic neuronal loss in the substantia nigra. HIF-1α is involved in various pathological mechanisms underlying PD, including α-synuclein aggregation, neuroinflammation, mitochondrial dysfunction, and proteasomal degradation. Emerging evidence from several preclinical studies demonstrates that HIF-1α could be a promising therapeutic target due to its active involvement in PD pathology. This review aims to elucidate the interconnection between hypoxia and the development of PD by evaluating the role of HIF-1α in the pathogenesis of PD and summarizing possible therapeutic strategies based on modifying the activity of the HIF-1α signaling.