High-altitude environments elevate central and peripheral α-synuclein levels and accelerate PD-related pathology

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 ro le 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.