Recombinant ovine prion protein can be mutated at position 136 to improve its efficacy as an inhibitor of prion propagation

Kopycka, Katarzyna; Maddison, Ben C.; Gough, Kevin C.

Abstract

Prion diseases are progressive neurodegenerative disorders with no effective therapeutics. The central event leading to the pathology in the diseases is the conversion of PrPC into PrPSc and its accumulation in the central nervous system. Previous studies demonstrated that recombinant PrP (rPrP) and PrP peptides can inhibit the formation of PrPSc. Here, the effectiveness of ovine rPrP mutants at codon 136 and peptides derived from this region were assessed for their ability to inhibit PrPSc replication, using protein misfolding cyclic amplification (PMCA). Based on a rPrP VRQ (rVRQ) genotype background (positions 136, 154 and 171) and mutations at position 136, the most effective inhibitors were V136R, V136K and V136P mutants, with IC50 values of 1 to 2 nM; activities much more potent than rVRQ (114 nM). rRRQ and rKRQ were also shown to effectively inhibit multiple ruminant prion amplification reactions that used distinct prion strain seeds and substrate PRNP genotypes. rRRQ, rKRQ and rPRQ were also shown to effectively protect Rov9 cells from scrapie infection when applied at 250 nM. The study demonstrates for the first time that the rPrP sequence can be mutated at sites known to be involved in prion disease susceptibility, to produce inhibitors with improved efficacy.

Citation

Kopycka, K., Maddison, B. C., & Gough, K. C. (2023). Recombinant ovine prion protein can be mutated at position 136 to improve its efficacy as an inhibitor of prion propagation. Scientific Reports, 13(1), Article 3452. https://doi.org/10.1038/s41598-023-30202-0

• Journal Article Type: Article
• Acceptance Date: Feb 17, 2023
• Online Publication Date: Mar 1, 2023
• Publication Date: 2023
• Deposit Date: Mar 2, 2023
• Publicly Available Date: Mar 2, 2023
• Journal: Scientific Reports
• Electronic ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 1
• Article Number: 3452
• DOI: https://doi.org/10.1038/s41598-023-30202-0
• Keywords: Multidisciplinary
• Public URL: https://nottingham-repository.worktribe.com/output/17942455
• Publisher URL: https://www.nature.com/articles/s41598-023-30202-0