Hypoxic Response and Adaptation in Parkinson's Disease
The mammalian brain had very high energy requirements and was extremely dependent on oxygen supply,it was therefore highly susceptible to hypoxia.Parkinson's disease(PD),a prevalent neurodegenerative disorder,was characterized primarily by the degeneration of dopaminergic neurons situated in the substantia nigra pars compacta of the midbrain,along with the formation of Lewy bodies.The potential molecular pathogenic mechanisms of PD primarily encompassed the misfolding and aggregation of α-synuclein,mitochondrial dysfunction,protein clearance disorder,neuroinflammation,and oxidative stress.Notably,mitochondrial dysfunction played a crucial role in the pathogenesis of PD.Severe cerebral hypoxia had the potential to expedite the progression of PD by influen-cing mitochondrial oxidative phosphorylation,oxidative stress,and dopamine metabolism.However,numerous studies had demonstrated that intermittent mild or moderate hypoxia could elicit adaptive responses at both cellular and physiological levels,involving many molecular mediators including HIFs and Nrf2,and ultimately enhance the resistance to inflammation and oxidation.Thus,the tolerance and survival rate of neurons to hypoxia,ischemia,mitochondrial dysfunction,oxidative stress and possible proteotoxic stress could be improved,which indicates that related targets could be studied to relieve the development of hypoxic-ischemic injury,mito-chondrial damage and protein aggregation.The connection between the pathophysiology of PD and hypoxia,as well as hypoxia adapta-tion and its key molecules were reviewed,providing a theoretical foundation for novel ideas in the development of neuroprotective drugs.
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