Perivascular spread of CSF-derived α-synuclein oligomers drives region-specific Parkinson’s-like pathology

While the level of α-synuclein oligomers (α-SOs) in the CSF of patients with Parkinson's disease (PD) is consistently increased, its pathogenic role in PD remains poorly understood. This study focuses on the role of CSF-derived α-SOs in PD pathology. We demonstrated that CSF-derived α-synuclein enters the brain via perivascular spaces, which was more abundant in the olfactory bulb (OB) than in the substantia nigra (SN). We also found that neuroinflammation was more pronounced in the OB than in the SN following α-SOs injection. α-SOs-treated mice exhibited an early and persistent loss of dopaminergic (DA) neurons in the OB, along with olfactory deficit. Conversely, DA neuron loss in the SN occurred later and was associated with motor dysfunction. Furthermore, reducing α-SOs dose alleviated OB pathology. These findings suggest that perivascular spread of CSF-derived α-SOs induces region-specific PD-like pathology, indicating that removing CSF-derived α-SOs could slow PD progression.