Plasminogen Stimulates Formation of Pathogenic Prion Clumps

Researchers have found that plasminogen, a protein used by the body to digest blood clots, stimulates the formation of prion clumps, abnormal protein formations that underlie chronic brain diseases such as bovine spongiform encephalopathy (mad cow disease) in cattle; Creutzfeldt-Jakob disease in humans; scrapie in sheep; and chronic wasting disease in cervids.

In order to study the relationship between prions and plasminogen, investigators at the University of Kentucky (Lexington, USA) conducted functional assays using a cell-free prion protein (PrP) conversion system known as protein misfolding cyclic amplification (PMCA) as well as looking at plasminogen in prion-infected cell lines.

They reported in the December 2010 issue of the FASEB Journal that plasminogen stimulated propagation of the protease-resistant scrapie PrP. Compared to control PMCA conducted without plasminogen, addition of plasminogen in PMCA using wild-type brain material significantly increased PrP conversion. PrP conversion in PMCA was substantially less efficient with plasminogen-deficient brain material than with wild-type material.
Stimulation of PrP conversion was specific for plasminogen and depended on plasminogen's kringle domains. This activity was eliminated by modification of plasminogen structure or interference with the PrP-plasminogen interaction. When added to cell cultures, plasminogen and kringles were found to promote PrP propagation in ScN2a and Elk 21+ cells.

"I hope that our study will aid in developing therapy for prion diseases, which will ultimately improve the quality of life of patients suffering from prion diseases," said senior author Dr. Chonsuk Ryou, professor of microbiology, immunology, and molecular genetics at the University of Kentucky. "Since prion diseases can lay undetected for decades, delaying the ability of the disease-associated prion protein to replicate by targeting the cofactor of the process could be a monumental implication for treatment."

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