Op-brai150350 1..14

Extracellular a-synuclein has been proposed as a crucial mechanism for induction of pathological aggregate formation in previously healthy cells. In vitro, extracellular a-synuclein is partially associated with exosomal vesicles. Recently, we have provided evidence that exosomal a-synuclein is present in the central nervous system in vivo. We hypothesized that exosomal a-synuclein species from patients with a-synuclein related neurodegeneration serve as carriers for interneuronal disease transmission. We isolated exosomes from cerebrospinal fluid from patients with Parkinson’s disease, dementia with Lewy bodies, progressive supranuclear palsy as a non-a-synuclein related disorder that clinically overlaps with Parkinson’s disease, and neurological controls. Cerebrospinal fluid exosome numbers, a-synuclein protein content of cerebrospinal fluid exosomes and their potential to induce oligomerization of a-synuclein were analysed. The quantification of cerebrospinal fluid exosomal a-synuclein showed distinct differences between patients with Parkinson’s disease and dementia with Lewy bodies. In addition, exosomal a-synuclein levels correlated with the severity of cognitive impairment in cross-sectional samples from patients with dementia with Lewy bodies. Importantly, cerebrospinal fluid exosomes derived from Parkinson’s disease and dementia with Lewy bodies induce oligomerization of a-synuclein in a reporter cell line in a dose-dependent manner. Our data suggest that cerebrospinal fluid exosomes from patients with Parkinson’s disease and dementia with Lewy bodies contain a pathogenic species of a-synuclein, which could initiate oligomerization of soluble a-synuclein in target cells and confer disease pathology.