Comparison of the Anti-Prion Mechanism of Four Different Anti-Prion Compounds, Anti-PrP Monoclonal Antibody 44B1, Pentosan Polysulfate, Chlorpromazine, and U18666A, in Prion-Infected Mouse Neuroblastoma Cells

• Yamasaki, Takeshi

• Suzuki, Akio

• Hasebe, Rie

• Horiuchi, Motohiro

抄録

Molecules that inhibit the formation of an abnormal　isoform of prion protein (PrPSc) in prion-infected　cells are candidate therapeutic agents for prion　diseases. Understanding how these molecules inhibit　PrPSc formation provides logical basis for proper　evaluation of their therapeutic potential. In this study, we extensively analyzed the effects of the anti-PrP monoclonal antibody (mAb) 44B1, pentosan polysulfate (PPS), chlorpromazine (CPZ) and U18666A on the intracellular dynamics of a cellular isoform of prion protein (PrPC) and PrPSc in prion-infected mouse neuroblastoma cells to re-evaluate the effects of those agents. MAb 44B1 and PPS rapidly reduced PrPSc levels without altering intracellular distribution of PrPSc. PPS did not change the distribution and levels of PrPC, whereas mAb 44B1 appeared to inhibit the trafficking of cell surface PrPC to organelles in the endocytic-recycling pathway that are thought to be one of the sites for PrPSc formation. In contrast, CPZ and U18666A initiated the redistribution of PrPSc from organelles in the endocytic-recycling pathway to late　endosomes/lysosomes without apparent changes in the distribution of PrPC. The inhibition of lysosomal function by monensin or bafilomycin A1 after the occurrence of PrPSc redistribution by CPZ or U18666A partly antagonized PrPSc degradation, suggesting that the transfer of PrPSc to late endosomes/lysosomes, possibly via alteration of the membrane trafficking machinery of cells, leads to PrPSc degradation. This study revealed that precise analysis of the　intracellular dynamics of PrPC and PrPSc provides important information for understanding the mechanism of anti-prion agents.

収録刊行物

• PLoS ONE

  PLoS ONE 9 (9), e106516-, 2014-09-02

  The Public Library of Science

詳細情報

• CRID: 1050282677650472576
• NII論文ID: 120005476205
• HANDLE: 2115/57265
• ISSN: 19326203
• 本文言語コード: en
• 資料種別: journal article
• データソース種別:
  • IRDB
  • CiNii Articles