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Dual function of plasmin(ogen) system in PrPSc propagation in vitro
Author(s) -
Mays Charles E.,
Kim Younghwan,
Titlow William,
Telling Glenn,
Ryou Chongsuk
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.851.6
Subject(s) - plasmin , in vitro , chemistry , microbiology and biotechnology , in vivo , prion protein , pathogenesis , function (biology) , biochemistry , enzyme , biology , immunology , disease , genetics , medicine
Prions are infectious particles that consist of the misfolded, disease‐associated prion protein, PrP Sc , serving as a template to convert the conformation of the cellular prion protein, PrP C . 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 PrP Sc propagation, we studied the changes of PrP Sc levels using in vitro systems with or without the addition of plasmin(ogen). Here, we demonstrate that plasminogen increased, but plasmin abolished, PrP Sc 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 PrP Sc formation are not clear yet, plasmin abolishes PrP Sc propagation by cleaving PrP C , which reduces the level of PrP C available for conversion. Our results provide evidence that the dual function of the plasmin(ogen) system regulates PrP Sc propagation.