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Chemically induced accumulation of GAGs delays PrP(Sc) clearance but prolongs prion disease incubation time.

Abstract
Prion diseases are a group of fatal neurodegenerative diseases affecting humans and animals. The only identified component of the infectious prion is PrP(Sc), an aberrantly folded isoform of PrP(C). 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 PrP(Sc) 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 PrP(Sc )with cells cultured with Tilorone. We found that while the initial incorporation of PrP(Sc) was similar in the treated and untreated cells, clearance of PrP(Sc) 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 PrP(Sc) in lysosomes and further stabilize the prion protein conformation. Over-stabilized PrP(Sc) molecules have been shown to comprise reduced converting activity.
AuthorsTehila Mayer-Sonnenfeld, Dana Avrahami, Yael Friedman-Levi, Ruth Gabizon
JournalCellular and molecular neurobiology (Cell Mol Neurobiol) Vol. 28 Issue 7 Pg. 1005-15 (Nov 2008) ISSN: 1573-6830 [Electronic] United States
PMID18350378 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antiviral Agents
  • Enzyme Inhibitors
  • Glycosaminoglycans
  • PrPSc Proteins
  • Quinacrine
  • Tilorone
Topics
  • Animals
  • Antiviral Agents (pharmacology)
  • CHO Cells
  • Central Nervous System (metabolism, physiopathology)
  • Cricetinae
  • Cricetulus
  • Enzyme Inhibitors (pharmacology)
  • Glycosaminoglycans (metabolism)
  • Infectious Disease Incubation Period
  • Lysosomes (drug effects, metabolism)
  • Metabolic Clearance Rate (drug effects, physiology)
  • Mice
  • Mice, Inbred C57BL
  • Neurons (metabolism, pathology)
  • PrPSc Proteins (drug effects, metabolism)
  • Prion Diseases (drug therapy, metabolism, physiopathology)
  • Protein Conformation (drug effects)
  • Quinacrine (pharmacology)
  • Subcellular Fractions
  • Tilorone (pharmacology)
  • Time Factors

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