Exosomal cell-to-cell transmission of alpha synuclein oligomers

Background: Aggregation of alpha-synuclein (syn) and resulting cytotoxicity is a hallmark of sporadic and familial Parkinsons disease (PD) as well as dementia with Lewy bodies, with recent evidence implicating oligomeric and pre-fibrillar forms of syn as the pathogenic species. Recent in vitro studies support the idea of transcellular spread of extracellular, secreted syn across membranes. The aim of this study is to characterize the transcellular spread of syn oligomers and determine their extracellular location. Results: Using a novel protein fragment complementation assay where syn is fused to non-bioluminescent amino-or carboxy-terminus fragments of humanized Gaussia Luciferase we demonstrate here that syn oligomers can be found in at least two extracellular fractions: either associated with exosomes or free. Exosome-associated syn oligomers are more likely to be taken up by recipient cells and can induce more toxicity compared to free syn oligomers. Specifically, we determine that syn oligomers are present on both the outside as well as inside of exosomes. Notably, the pathway of secretion of syn oligomers is strongly influenced by autophagic activity. Conclusions: Our data suggest that syn may be secreted via different secretory pathways. We hypothesize that exosome-mediated release of syn oligomers is a mechanism whereby cells clear toxic syn oligomers when autophagic mechanisms fail to be sufficient. Preventing the early events in syn exosomal release and uptake by inducing autophagy may be a novel approach to halt disease spreading in PD and other synucleinopathies.