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

Abstract

Aggregated α-synuclein (α-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 α-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 (PSMαs). Here, we studied the kinetics of α-syn aggregation under quiescent conditions in the presence or absence of four different PSMα peptides and observed a remarkable shortening of the lag phase in their presence. Whereas pure α-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 PSMα peptides resulted in an almost immediate increase in the Thioflavin T (ThT) fluorescence. Despite similar peptide sequences, the different PSMα peptides displayed distinct effects on the kinetics of α-syn aggregation. Kinetic analyses of the data suggest that all four peptides catalyze α-syn aggregation through heterogeneous primary nucleation. The immunogold electron microscopic analyses showed that the aggregates were fibrillar and composed of α-syn. In addition of the co-aggregated materials to a cell model expressing the A53T α-syn variant fused to GFP was found to catalyze α-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.

Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils

“…refs. [55][56][57][58], is a well-known phenomenon that is postulated to exacerbate amyloid pathology 59 .…”

Approaching the Gut and Nasal Microbiota in Parkinson’s Disease in the Era of the Seed Amplification Assays

“…Indeed, the gut microbiota produces several “amyloid” molecules, including the “curli” protein, expressed in abundance from intestinal strains such as Escherichia coli and the phenol soluble modulins (PSMαs) produced from Staphylococcus aureus. In transgenic mice that overexpress human α-syn, the colonization with E. coli could promote α-syn D formation in the gut and its propagation to the brain, while, in vitro studies showed that the presence of PSMαs catalyzes α-syn aggregation [ 103 , 104 , 105 ]. Alterations of gut microbiota can lead to other important pathological processes associated with the disease.…”

Cytotoxic Staphylococcus aureus PSMα3 inhibits the aggregation of human insulin in vitro

“…6,18 PSM peptides are also well recognised for their predisposition to cross-interact with other amyloidogenic proteins, modulating fibrillation of each other, which can result in both aggregation acceleration and inhibition. [19][20][21] Furthermore, extensive polymorphism of PSM-composed amyloid-like structures was also shown to be determined by their cross-seeded interactions during the biofilm formation process. 9,19 There is quite ambiguous data concerning the effects of the crossinteraction of PSMs with some human amyloids.…”

“…9,19 There is quite ambiguous data concerning the effects of the crossinteraction of PSMs with some human amyloids. 20,21 For example, N-terminally formylated PSMa peptides were described previously to accelerate fibrillation of a-synuclein (a-syn) in human cells as well as in vitro under conditions that mimic physiological. 20 On the other hand, the opposite effect of PSMa3 on a-syn fibril formation was described previously.…”

“…20,21 For example, N-terminally formylated PSMa peptides were described previously to accelerate fibrillation of a-synuclein (a-syn) in human cells as well as in vitro under conditions that mimic physiological. 20 On the other hand, the opposite effect of PSMa3 on a-syn fibril formation was described previously. 21 Moreover, the a-helical structure of PSMa3-like peptides was revealed to be a crucial factor in inhibiting a-syn aggregation, and mutations in the a-helix scaffold resulted in full loss of the anti-fibrillation effect.…”