High-altitude environments elevate central and peripheral α-synuclein levels and accelerate PD-related pathology.
14 affiliations
- 1Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Army Medical University, Chongqing, China.
- 2Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China.
- 3Institute of Brain and Intelligence, Army Medical University, Chongqing, China.
- 4Department of Special Medicine, Daping Hospital, Army Medical University, Chongqing, China.
- 5Shigatse Branch, Xinqiao Hospital, Army Medical University, Shigatse, China.
- 6Department of Neurology, The Second Affiliated Hospital, Xinqiao Hospital, Army Medical University, Chongqing, China.
- 7Department of Neurology, The 910th Hospital of the Joint Logistics Support Force of the Chinese PLA, Quanzhou, Fujian Province, China.
- 8Department of Neurology, Army 73rd Group Military Hospital of the Chinese PLA, Xiamen, Fujian Province, China.
- 9Shigatse Branch, Xinqiao Hospital, Army Medical University, Shigatse, China. [email protected].
- 10Tibet Autonomous Region, No. 5 Zhufeng West Road, Shigatse, China. [email protected].
- 11Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Army Medical University, Chongqing, China. [email protected].
- 12Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China. [email protected].
- 13Institute of Brain and Intelligence, Army Medical University, Chongqing, China. [email protected].
- 14, No. 10 Changjiang Branch Road, Yuzhong District, Chongqing, China. [email protected].
Abstract
Background
High-altitude exposure has been linked to an increased risk of Parkinson's disease (PD), potentially through hypoxic neuronal damage, yet the involvement of α-synuclein (α-syn) remains poorly understood. This study integrates population-based surveys, animal experiments, and clinical cross-sectional data to elucidate the role of high-altitude environments in PD pathogenesis.Methods
A cross-sectional study was conducted among middle-aged and elderly high-altitude residents. Additional cohorts (low-altitude PD patients, low-altitude controls, and high-altitude controls) were enrolled for plasma and erythrocytic α-syn measurement, and a subset of PD patients underwent transcranial sonography to assess correlations between erythrocyte indices and substantia nigra echogenicity. A53T transgenic mice were exposed to high altitude for six months and evaluated by behavioral tests, omics sequencing, α-syn assays, and immunohistochemistry. Erythrocyte-derived extracellular vesicles from PD patients were intravenously injected into wild-type mice to assess brain entry.Results
The crude prevalence of PD tended to be higher in high-altitude populations than the national average. A53T mice exposed to high altitude displayed more severe motor deficits, elevated brain α-syn levels, and pronounced dopaminergic neuron loss. Omics analyses revealed enrichment of pathways related to IL-17, sphingosine-1-phosphate signaling, and oxidative stress in brain tissue from high-altitude versus low-altitude A53T mice, suggesting blood-brain barrier disruption and impaired α-syn clearance. In peripheral blood, both high-altitude mice and humans exhibited elevated α-syn levels compared with their low-altitude counterparts, and erythrocyte indices correlated positively with α-syn levels. After normalization to erythrocyte count and hemoglobin, however, erythrocytic α-syn did not differ between high-altitude and low-altitude controls. In mice, intravenously injected human-derived erythrocytic vesicles entered the brain.Conclusions
Chronic high‑altitude exposure is associated with peripheral and central α‑syn accumulation, which may be driven by a hypoxia‑induced erythrocyte pool expansion and increased α-syn burden, potentially aggravating PD‑related neuropathology.
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BibTeX
@article{sun2026highaltitude,
title = {{High-altitude environments elevate central and peripheral α-synuclein levels and accelerate PD-related pathology.}},
author = {Hao-Lun Sun and Dong-Yu Fan and Jun-Hao Xie and Qing Du and Rui-Jie Zeng and Jian-Ni Hu and Jun Liang and Li Zhu and Xu Wang and Hao-Xiang Wang and Qing Zhao and Rong Zhang and Yan-Jiang Wang and Hong-Da Zhao and Wang-Sheng Jin},
journal = {Journal of translational medicine},
year = {2026},
month = oct,
doi = {10.1186/s12967-026-09103-z},
url = {https://europepmc.org/article/MED/42963787},
note = {CC BY},
}
RIS
TY - JOUR
TI - High-altitude environments elevate central and peripheral α-synuclein levels and accelerate PD-related pathology.
AU - Hao-Lun Sun
AU - Dong-Yu Fan
AU - Jun-Hao Xie
AU - Qing Du
AU - Rui-Jie Zeng
AU - Jian-Ni Hu
AU - Jun Liang
AU - Li Zhu
AU - Xu Wang
AU - Hao-Xiang Wang
AU - Qing Zhao
AU - Rong Zhang
AU - Yan-Jiang Wang
AU - Hong-Da Zhao
AU - Wang-Sheng Jin
PY - 2026
DA - 2026/10/21
JO - Journal of translational medicine
DO - 10.1186/s12967-026-09103-z
UR - https://europepmc.org/article/MED/42963787
AB - Background High-altitude exposure has been linked to an increased risk of Parkinson's disease (PD), potentially through hypoxic neuronal damage, yet the involvement of α-synuclein (α-syn) remains poorly understood. This study integrates population-based surveys, animal experiments, and clinical cross-sectional data to elucidate the role of high-altitude environments in PD pathogenesis.Methods A cross-sectional study was conducted among middle-aged and elderly high-altitude residents. Additional cohorts (low-altitude PD patients, low-altitude controls, and high-altitude controls) were enrolled for plasma and erythrocytic α-syn measurement, and a subset of PD patients underwent transcranial sonography to assess correlations between erythrocyte indices and substantia nigra echogenicity. A53T transgenic mice were exposed to high altitude for six months and evaluated by behavioral tests, omics sequencing, α-syn assays, and immunohistochemistry. Erythrocyte-derived extracellular vesicles from PD patients were intravenously injected into wild-type mice to assess brain entry.Results The crude prevalence of PD tended to be higher in high-altitude populations than the national average. A53T mice exposed to high altitude displayed more severe motor deficits, elevated brain α-syn levels, and pronounced dopaminergic neuron loss. Omics analyses revealed enrichment of pathways related to IL-17, sphingosine-1-phosphate signaling, and oxidative stress in brain tissue from high-altitude versus low-altitude A53T mice, suggesting blood-brain barrier disruption and impaired α-syn clearance. In peripheral blood, both high-altitude mice and humans exhibited elevated α-syn levels compared with their low-altitude counterparts, and erythrocyte indices correlated positively with α-syn levels. After normalization to erythrocyte count and hemoglobin, however, erythrocytic α-syn did not differ between high-altitude and low-altitude controls. In mice, intravenously injected human-derived erythrocytic vesicles entered the brain.Conclusions Chronic high‑altitude exposure is associated with peripheral and central α‑syn accumulation, which may be driven by a hypoxia‑induced erythrocyte pool expansion and increased α-syn burden, potentially aggravating PD‑related neuropathology.
SN - 1479-5876
ER -