Prion diseases are a group of fatal neurodegenerative diseases affecting humans and animals. The only identified component of the infectious prion is PrPSc, an aberrantly folded isoform of PrPC. Glycosaminoglycans, which constitute the main receptor for prions on cells, play a complex role in the pathogenesis of prion diseases. For example, while agents inducing aberrant lysosomal accumulation of GAGs such as Tilorone and Quinacrine significantly reduced PrPSc content in scrapie-infected cells, administration of Quinacrine to prion-infected subjects did not improve their clinical status. In this study, we investigated the association of PrPSc with cells cultured with Tilorone. We found that while the initial incorporation of PrPSc was similar in the treated and untreated cells, clearance of PrPSc from the Tilorone-treated cells was significantly impaired. Interestingly, prolonged administration of Tilorone to mice prior to prion infection resulted in a significant delay in disease onset, concomitantly with in vivo accumulation of lysosomal GAGs. We hypothesize that GAGs may complex with newly incorporated PrPSc in lysosomes and further stabilize the prion protein conformation. Over-stabilized PrP Sc molecules have been shown to comprise reduced converting activity.
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Acknowledgments This work was supported by the EC neuroprion grant FOOD-CT-2004-506579, the Horowitz Foundation, and the Israely government office for science and culture.
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