CNS neuroscience & therapeutics · 2022
Hypoxic stress accelerates the propagation of pathological alpha-synuclein and degeneration of dopaminergic neurons.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Guo Mengyuan, Liu Weijin, Luo Hanjiang, Shao Qianqian, Li Yuning, Gu Yakun, Guan Yuying, Ma Wei, Chen Min, Yang Hui, Ji Xunming, Liu Jia
Аннотация
AIMS: The etiology of Parkinson's disease (PD) is complex and the mechanism is unclear. It has become a top priority to find common factors that induce and affect PD pathology. We explored the key role of hypoxia in promoting the pathological propagation of α-synuclein (α-syn) and the progression of PD.
METHODS: We performed PD modeling by conducting intracranial stereotaxic surgery in the unilateral striatum of mice. We then measured protein aggregation in vitro. The rotarod and pole tests were employed next to measure the damage of the phenotype. Pathological deposition and autophagy were also observed by immunofluorescence staining and protein levels measured by western blotting.
RESULTS: We demonstrated that short-term hypoxia activated phosphorylated (p)-α-syn in mice. We confirmed that p-α-syn was more readily formed aggregates than α-syn in vitro. Furthermore, we found that hypoxia promoted the activation and propagation of endogenous α-syn, contributing to the earlier degeneration of dopaminergic neurons in the substantia nigra and the deposition of p-α-syn in our animal model. Finally, autophagy inhibition contributed to the above pathologies.
CONCLUSION: Hypoxia was shown to accelerate the pathological progression and damage phenotype in PD model mice. The results provided a promising research target for determining common interventions for PD in the future.
METHODS: We performed PD modeling by conducting intracranial stereotaxic surgery in the unilateral striatum of mice. We then measured protein aggregation in vitro. The rotarod and pole tests were employed next to measure the damage of the phenotype. Pathological deposition and autophagy were also observed by immunofluorescence staining and protein levels measured by western blotting.
RESULTS: We demonstrated that short-term hypoxia activated phosphorylated (p)-α-syn in mice. We confirmed that p-α-syn was more readily formed aggregates than α-syn in vitro. Furthermore, we found that hypoxia promoted the activation and propagation of endogenous α-syn, contributing to the earlier degeneration of dopaminergic neurons in the substantia nigra and the deposition of p-α-syn in our animal model. Finally, autophagy inhibition contributed to the above pathologies.
CONCLUSION: Hypoxia was shown to accelerate the pathological progression and damage phenotype in PD model mice. The results provided a promising research target for determining common interventions for PD in the future.