Serum exosomes contain filamentous alpha-synuclein and facilitate the propagation of Parkinson’s pathology

Abstract

Parkinson’s disease (PD) is pathologically characterized by the deposition of a-synuclein (a-syn) containing Lewy bodies/neurites in both the central nervous system (CNS) and the peripheral nervous system (PNS). Recent evidence indicates the contribution of exosomes, nano-sized extracellular vesicles, to the dissemination of Lewy pathology in the PNS into the CNS and vice versa. We analyzed serum exosomes from patients with PD (n = 142), multiple system atrophy (MSA) (n = 18), progressive supranuclear palsy (PSP) (n = 28), rapid eye movement sleep behavior disorder (n = 31), and controls (n = 105). Although the number of exosomes significantly decreased in PD compared to controls (p = 0.002), the filamentous α-syn in exosomes quantified by our ELISA system significantly increased in PD compared to controls (p < 0.0001) and compared to MSA (p = 0.03) or PSP (p = 0.04). Further analysis revealed that exosomes facilitate the propagation of filamentous α-syn between neurons and from the PNS to the CNS. These results highlight that the serum exosomal a-syn filaments may reflect peripheral Lewy pathology and that exosomes can enhance the propagation into the CNS.