Hypoxia and Alpha-Synuclein: Inextricable Link Underlying the Pathologic Progression of Parkinson's Disease

Guo, Mengyuan; Ji, Xunming; Liu, Jia

doi:10.3389/fnagi.2022.919343

Cited by 21 publications

(15 citation statements)

References 206 publications

(222 reference statements)

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“…Our previous studies have shown that long-term hypoxia can damage nerve function and promote the transformation of α-syn into p-α-syn and its subsequent accumulation in the brain[48] [49]. In the present study, we found nerve damage and p-α-syn accumulation around the damaged area in the brain of both IS and simple hypoxia injury model mice.…”

Section: Discussionsupporting

confidence: 67%

Serum phosphorylated α-synuclein: A potential biomarker of poststroke cognitive impairment

Wang

et al. 2023

Preprint

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Background Ischemic stroke (IS) is characterized by cerebral infarction caused by acute cerebral vascular occlusion, with high rates of morbidity, mortality, and disability. Poststroke cognitive impairment, one of the major secondary impairments, is associated with greatly reduced quality of life in many patients with IS. Because poststroke cognitive impairment has insidious onset and progressive progression, the development of early warning biomarkers is essential for this disease. Methods In this study, we detected phosphorylated α-synuclein (p-α-syn) pathology in the brain of distal middle cerebral artery occlusion (dMCAO) mice and hypoxia mice. We collected blood samples and routine biochemistry data of patients with IS and those who underwent physical examination in Beijing Boai Hospital from July to December 2021. We examined the serum level of p-α-syn in those people by ELISA. Results The level of p-α-syn was significantly increased and showed pathological aggregation around the cerebral infarct in dMCAO mice. And the similar aggregation in neurons were also observed in the brain of chronic hypoxia mice, thus suggesting that hypoxia is the internal cause of α-syn pathology. The serum level of p-α-syn in patients with IS was significantly lower than that of control group, and this lower serum level was positively correlated with the cognitive level of these patients. Further association analysis revealed that the decrease in the serum high-density lipoprotein level of patients with stroke was significantly correlated with their decreased p-α-syn level. Conclusions Serum p-α-syn has the potential to serve as a biomarker for poststroke cognitive impairment.

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Section: Discussionsupporting

confidence: 67%

Serum phosphorylated α-synuclein: A potential biomarker of poststroke cognitive impairment

Wang

et al. 2023

Preprint

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“…Our previous study found that hypoxia is a common factor of various pathogenic factors of PD 36 . It is a new perspective to interpret PD from the perspective of hypoxia.…”

Section: Discussionmentioning

confidence: 90%

“…Some studies have proposed that the pathogenesis of PD can be divided into three stages, which are related to triggers, facilitators, and aggravators, respectively 53 . As a common feature of various PD pathogenesis factors, 36 hypoxia may be a key mechanism in PD, which still needs further discussion. This study provides reliable evidence for subsequent studies, providing a promising research perspective for the intervention of PD.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study found that hypoxia is a common factor of various pathogenic factors of PD. 36 It is a new perspective to interpret PD from the perspective of hypoxia. The results of epidemiological studies have shown that aging is an important factor in increasing the incidence of PD, and that the incidence of PD increases 5-10 times after the age of 65.…”

Section: Discussionmentioning

confidence: 99%

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Hypoxic stress accelerates the propagation of pathological alpha‐synuclein and degeneration of dopaminergic neurons

et al. 2022

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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.

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“…The recent WATCH-PD study used the same software analysis (BrainBaseline ™) to successfully correlate symptoms in Parkinson’s Disease patients with a similar range of movement biomarkers at sea level [10]. Hypoxia may also be a key factor in the pathogenesis of Parkinson’s Disease [28].…”

Section: Discussionmentioning

confidence: 99%

A feasibility study of smartphone sensors to assess the effect of acute high altitude (3,800 m) exposure on cognition and motor function in healthy participants

Goldman,

Dubowitz,

Anderson

2023

Preprint

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Acute exposure to hypoxia at attitude has neurologic effects. Some subjects develop severe neurologic symptoms, including Parkinsonism, when hypoxic at high altitude as part of an Acute Mountain Sickness syndrome. Digital health technologies can provide continuous monitoring and objective, real-world measures of movement disorders, but only limited validation data of wearable sensors is available in the high-altitude setting. This equipment validation and feasibility study assessed smartphone microphone and accelerometer function at sea level and 12470 feet (3,800 m) to assess their potential value to predict and prevent neurologic features of acute mountain sickness. A feasibility study of standardized assessments of motor, speech and cognitive tasks was performed in 3 normal subjects at sea level and at altitude. All subjects were hypoxic at altitude with O2saturations ranging from 77-81%. Shaker table (range of frequencies) and high-fidelity speaker (range of frequencies) controls confirmed high correlation of observed and expected measurements for microphone and accelerometer under all conditions. The feasibility study demonstrated that under conditions of hypoxia at attitude, fine motor skills are impaired; visual short-term memory is not impaired but has longer response time; gait and balance is impaired, and a postural tremor develops with frequencies below 10 Hz. Future studies could use these wearable sensors to further assess effects at altitude of more severe hypoxia with applications in the high-altitude environment for Parkinson’s Disease patients, with further opportunity for aviation and military use.

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Hypoxia and Alpha-Synuclein: Inextricable Link Underlying the Pathologic Progression of Parkinson's Disease

Cited by 21 publications

References 206 publications

Serum phosphorylated α-synuclein: A potential biomarker of poststroke cognitive impairment

Serum phosphorylated α-synuclein: A potential biomarker of poststroke cognitive impairment

Hypoxic stress accelerates the propagation of pathological alpha‐synuclein and degeneration of dopaminergic neurons

A feasibility study of smartphone sensors to assess the effect of acute high altitude (3,800 m) exposure on cognition and motor function in healthy participants

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