Prion peptide (PrP) misfolds to infectious
scrapie isoform, the β pleat-rich insoluble fibrils responsible for neurodegeneration and fatal conformational diseases in humans. The amino acid sequence 106-126 from
prion proteins, PrP(106-126), is highly amyloidogenic and implicated in
prion-induced pathologies. Here, we report a novel interaction between PrP(106-126) and the thrombogenic
plasma protein fibrinogen that can lead to mitigation of
prion-mediated pro-thrombotic responses in human platelets as well as significant decline in neuronal toxicity. Thus, prior exposure to
fibrinogen-restrained PrP-induced rise in cytosolic
calcium,
calpain activation, and shedding of extracellular vesicles in platelets while it, too, averted cytotoxicity of neuronal cells triggered by
prion peptide. Interestingly, PrP was found to accelerate
fibrin-rich clot formation, which was resistant to
plasmin-mediated fibrinolysis, consistent with enhanced
thrombus stability provoked by PrP. We propose that PrP-
fibrinogen interaction can be clinically exploited further for prevention and management of infectious
prion related disorders. Small molecules or
peptides mimicking PrP-binding sites on
fibrinogen can potentially mitigate PrP-induced cellular toxicity while also preventing the negative impact of PrP on
fibrin clot formation and lysis.