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Dual function of plasmin(ogen) system in PrPSc propagation in vitro

Prions are infectious particles that consist of the misfolded, disease‐associated prion protein, PrPSc, serving as a template to convert the conformation of the cellular prion protein, PrPC. Many lines of evidence suggest that a co‐factor is involved in the conversion process. Recently, kringle domains of plasminogen were identified to interact with PrP. However, the in vivo importance of this interaction in prion pathogenesis remains inconclusive: One study showed a modest prolongation, but another demonstrated a significant decrease of incubation period in plasminogen null mice infected by prions. To investigate the role of plasmin(ogen) system in PrPSc propagation, we studied the changes of PrPSc levels using in vitro systems with or without the addition of plasmin(ogen). Here, we demonstrate that plasminogen increased, but plasmin abolished, PrPSc propagation during protein misfolding cyclic amplification as well as in a prion‐infected cell culture model. The assays inhibiting the interaction of plasminogen with PrP and enzymatic activity of plasmin reversed the induced effects. Although mechanistic details of plasminogen‐induced PrPSc formation are not clear yet, plasmin abolishes PrPSc propagation by cleaving PrPC, which reduces the level of PrPC available for conversion. Our results provide evidence that the dual function of the plasmin(ogen) system regulates PrPSc propagation.