Prion diseases are associated with the conformational conversion of the cellular prion protein (PrP(C)) into the pathological scrapie isoform (PrP(Sc)) in the brain. Both the in vivo and in vitro conversion of PrP(C) into PrP(Sc) is significantly inhibited by differences in amino acid sequence between the two molecules. Using protein misfolding cyclic amplification (PMCA), we now report that the recombinant full-length human PrP (rHuPrP23-231) (that is unglycosylated and lacks the glycophosphatidylinositol anchor) is a strong inhibitor of human prion propagation. Furthermore, rHuPrP23-231 also inhibits mouse prion propagation in a scrapie-infected mouse cell line. Notably, it binds to PrP(Sc), but not PrP(C), suggesting that the inhibitory effect of recombinant PrP results from blocking the interaction of brain PrP(C) with PrP(Sc). Our findings suggest a new avenue for treating prion diseases, in which a patient's own unglycosylated and anchorless PrP is used to inhibit PrP(Sc) propagation without inducing immune response side effects.
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http://dx.doi.org/10.1038/srep02911 | DOI Listing |
Proc Natl Acad Sci U S A
December 2024
Laboratory for Protein Conformation Diseases, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan.
The dynamic balance between formation and disaggregation of amyloid fibrils is associated with many neurodegenerative diseases. Multiple chaperones interact with and disaggregate amyloid fibrils, which impacts amyloid propagation and cellular phenotypes. However, it remains poorly understood whether and how site-specific binding of chaperones to amyloids facilitates the concerted disaggregation process and modulates physiological consequences in vivo.
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View Article and Find Full Text PDFJ Clin Invest
December 2024
The transmissible nature of prion diseases enables reproduction of neurodegeneration in small animal models that faithfully follows the disease process observed in the natural disease of animals and humans. This allows the temporal development of disease to be investigated and correlated with pathology in a complex brain environment. In this issue of the JCI, Makarava et al.
View Article and Find Full Text PDFMol Neurodegener
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Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Brain Sci
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Department of Life Sciences, University of Trieste, Via A. Valerio, 28, 34127 Trieste, Italy.
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