The Bacterial Amyloids Phenol Soluble Modulins from Staphylococcus aureus Catalyze Alpha-Synuclein Aggregation

Aggregated alpha-synuclein (alpha-syn) is the main constituent of Lewy bodies, which are a pathological hallmark of Parkinson's disease (PD). Environmental factors are thought to be potential triggers capable of initiating the aggregation of the otherwise monomeric alpha-syn. Braak's seminal work redirected attention to the intestine and recent reports of dysbiosis have highlighted the potential causative role of the microbiome in the initiation of pathology of PD. Staphylococcus aureus is a bacterium carried by 30-70% of the general population. It has been shown to produce functional amyloids, called phenol soluble modulins (PSM alpha s). Here, we studied the kinetics of alpha-syn aggregation under quiescent conditions in the presence or absence of four different PSM alpha peptides and observed a remarkable shortening of the lag phase in their presence. Whereas pure alpha-syn monomer did not aggregate up to 450 h after initiation of the experiment in neither neutral nor mildly acidic buffer, the addition of different PSM alpha peptides resulted in an almost immediate increase in the Thioflavin T (ThT) fluorescence. Despite similar peptide sequences, the different PSM alpha peptides displayed distinct effects on the kinetics of alpha-syn aggregation. Kinetic analyses of the data suggest that all four peptides catalyze alpha-syn aggregation through heterogeneous primary nucleation. The immunogold electron microscopic analyses showed that the aggregates were fibrillar and composed of alpha-syn. In addition of the co-aggregated materials to a cell model expressing the A53T alpha-syn variant fused to GFP was found to catalyze alpha-syn aggregation and phosphorylation in the cells. Our results provide evidence of a potential trigger of synucleinopathies and could have implications for the prevention of the diseases.