Cerebrospinal fluid and dural accumulation of α-synuclein impairs CNS clearance in Parkinson’s disease

Parkinson’s disease (PD) is characterized by the build-up of α-synuclein (α-syn) in the brain, where it drives neurodegeneration. Importantly, aggregated α-syn also accumulates in the cerebrospinal fluid (CSF) of PD patients, and while increasingly used for diagnosis, its pathological role remains poorly understood. Here, we demonstrate that α-syn accumulation in central nervous system (CNS) border tissues promotes CNS clearance deficits, as observed in PD patients. We find that aggregated α-syn accumulates not only in the CSF but also in the dura mater of individuals with PD, and, using acute and chronic mouse models, show that α-syn deposition in these sites induces immune alterations in CNS borders and disrupts CNS clearance. Mechanistically, we reveal that α-syn at CNS borders elevates CSF TNF and demonstrate that both TNF and α-syn aggregates themselves impair lymphatic endothelial cell function. These findings demonstrate a pathological role for α-syn in the CNS border tissues and position meningeal immunity as a contributor to CNS clearance deficits in PD pathogenesis.