Parkinson's disease beyond the brain: erythrocyte α-synuclein transfer across the blood-brain barrier

Parkinson's disease is characterized by the accumulation and propagation of α-synuclein pathology in the central nervous system, yet the contribution of peripheral α-synuclein sources remains unclear. Here, we identify erythrocytes as an important reservoir of α-synuclein and demonstrate that bone marrow-derived erythrocytic α-synuclein likely contributes to brain pathology and Parkinson's disease-related neurodegeneration. Using human tissues and mouse models, we show that erythrocytes harbour abundant α-synuclein species. Bone marrow transplantation revealed widespread distribution of bone marrow-derived α-synuclein in peripheral organs, with detectable but substantially lower levels in the brain. Within the central nervous system, bone marrow-derived α-synuclein preferentially accumulated in resident microglia, as confirmed by immunophenotyping and single-nucleus RNA Sequencing, and was associated with microglial activation. Furthermore, erythrocyte-derived extracellular vesicles carrying α-synuclein can be readily taken up by microglia in vivo. Functionally, elevated levels of bone marrow-derived α-synuclein in the mouse brain resulted in dopaminergic dysfunction with a mild neurodegenerative phenotype under baseline conditions. Importantly, blood-brain barrier integrity critically regulated peripheral α-synuclein entry into the central nervous system. Disruption of the blood-brain barrier by endotoxin administration, mannitol treatment or focused ultrasound markedly increased the entry of peripheral α-synuclein into the brain, aggravating neurodegeneration and behavioural deficits. Collectively, these findings identify bone marrow-derived erythrocytic α-synuclein as a systemic contributor to the pathogenesis of Parkinson's disease and highlight blood-brain barrier integrity as a key permissive regulator of peripheral-to-central α-synuclein transmission.