Fibrinogen Mitigates Prion-Mediated Platelet Activation and Neuronal Cell Toxicity

Background: Prion peptide (PrP) is known to mediate neurotoxicity and fatal conformational diseases, as well as platelet activation signaling. Fibrinogen is a thrombogenic peptide circulating in abundance in blood. Methods: Interaction between plasma fibrinogen and PrP(106-126) was examined using surface plasmon resonance. To evaluate the effect of this interaction, intracellular calcium, extracellular vesicle release, calpain activity and talin degradation were studied in platelets and cell viability, as well as mitochondrial membrane potential were investigated in neuronal cells. Fibrin-clot formation and fibrinolysis in presence of PrP(106-126) were studied under confocal microscope. Findings: 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. Remarkably, PrP, on the other hand, accelerated fibrin-rich clot formation that was resistant to plasmin-mediated fibrinolysis, thus contributing to enhanced thrombus stability. Interpretation: The interaction between PrP and fibrinogen reverses PrP (106-126)-induced platelet activation and neurotoxicity while prion peptide, on the other hand, alters the morphology of fibrin clot making it more resistant to lysis. This interaction can be exploited to develop small-molecule pharmacological modulators mimicking PrP-binding sites on fibrinogen that may attenuate the adverse effects of prion, on both platelets as well as neuronal cells. Funding Information: This research was supported by Indian Council of Medical Research under CAR, Department of Biotechnology, Science and Engineering Research Board, and a J.C. Bose National fellowship received by D. Dash from the Government of India. Declaration of Interests: None. Ethics Approval Statement: Informed written consent was obtained, strictly as per the recommendations and approval of the Institutional Ethical Committee of Banaras Hindu University. The study methodologies were conformed to the standards set by the Declaration of Helsinki.