Bone marrow-derived a-synuclein exacerbates Parkinson's disease through blood-brain barrior disruption

Parkinson's disease (PD) is classically defined by a-synuclein pathology within the brain. However, the origin of a-synuclein remains unclear. To investigate whether peripheral sources contribute to a-synuclein pathology, we employed a novel Vav1-SNCA mouse model, in which human SNCA-A53T is selectively expressed under the Vav1-cre promoter. Bone marrow (BM) was harvested from these mice and wild-type (WT) controls, then rigorously depleted of T-cells to isolate hematopoietic populations. Following whole-body X-ray irradiation to ablate endogenous hematopoiesis in recipient WT mice, the T-cell-depleted BM was intravenously transplanted via tail vein injection. We performed single-nucleus RNA sequencing (snRNA-seq) on post-transplantation brain tissue. Our findings reveal a pivotal role for bone marrow-derived a-synuclein in disease pathogenesis, identifying erythrocytes as the primary reservoir for this protein. These results redefine our understanding of a-synuclein propagation, positioning the bone marrow as a critical source of pathogenic protein and offering new therapeutic targets for intervention.