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Cationic Lipopolyamines Induce Degradation of PrPSc in Scrapie-Infected Mouse Neuroblastoma Cells

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Published/Copyright: July 5, 2005
Biological Chemistry
From the journal Volume 381 Issue 5-6

Abstract

In prion diseases the endogenous prion protein (PrPC) is converted into an abnormally folded isoform, denoted PrPSc, which represents the major component of infectious scrapie prions. The mechanism of the conversion is largely unknown, but the conversion is thought to occur after PrPC has reached the plasma membrane. Here we show that exogenous adminstration of the cationic lipopolyamine DOSPA interfered with the accumulation of PrPSc in scrapie-infected neuroblastoma cells. Structural analysis of the compounds tested revealed that inhibition of PrPSc was specific for lipids with a headgroup composed of the polyamine spermine and a quarternary ammonium ion between the headgroup and the lipophilic tail. The cationic lipopolyamine DOSPA induced the cellular degradation of preexisting PrPSc aggregates within 12 hours and interfered with the de novo synthesis of PrPSc. Biosynthesis of PrPC, or the assembly of sphingolipid-cholesterol microdomains (rafts) on the plasma membrane, were not affected by this inhibitor. After removal of DOSPA and replating into normal medium propagation of PrPSc commenced, although initially at a reduced rate. Incubation of ScN2a cells in free spermidine had no inhibitory effect on the accumulation of PrPSc. Our results indicate that membrane targeting of a small polyamine molecule creates a potent inhibitor of PrPSc propagation and offers the possibility to degrade preexisting PrPSc aggregates in living cells.

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Published Online: 2005-07-05
Published in Print: 2000-06-21

Copyright (c) 2000 by Walter de Gruyter GmbH & Co. KG

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  2. Signal Transduction and Post-Transcriptional Gene Expression
  3. Regulation of GTPases in the Bacterial Translation Machinery
  4. GTPase Mechanisms and Functions of Translation Factors on the Ribosome
  5. The Role of Heterotrimeric G Proteins in Platelet Activation
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  7. Nogo-A, a Potent Inhibitor of Neurite Outgrowth and Regeneration
  8. Rho GTPases as Targets of Bacterial Protein Toxins
  9. A Conserved Gβ Binding (GBB) Sequence Motif in Ste20p/PAK Family Protein Kinases
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  11. Theoretical Description of the Direct Exponential Amplification and Sequencing (DEXAS) Method
  12. Adenine Nucleotide N-Glycosidase Activity of the A-Chain of Cinnamomin Characterized by 1H-Nuclear Magnetic Resonance
  13. Msb4p, a Protein Involved in Cdc42p-Dependent Organization of the Actin Cytoskeleton, Is a Ypt/Rab-Specific GAP
  14. Muscle Phosphorylase Kinase Is Not a Substrate of AMP-Activated Protein Kinase
  15. Cationic Lipopolyamines Induce Degradation of PrPSc in Scrapie-Infected Mouse Neuroblastoma Cells
  16. Glycosylphosphatidylinositol-Specific Phospholipase D of Human Serum Activity Modulation by Naturally Occurring Amphiphiles
  17. Retrieval of the mrp2 Gene Encoded Conjugate Export Pump from the Canalicular Membrane Contributes to Cholestasis Induced by tert-Butyl Hydroperoxide and Chloro-Dinitrobenzene
  18. Matrix Metalloproteinases-2, -3, -7, -9 and -10, But Not MMP-11, Are Differentially Expressed in Normal, Benign Tumorigenic and Malignant Human Keratinocyte Cell Lines
  19. Human Keratinocyte Cell Lines Differ in the Expression of the Collagenolytic Matrix Metallo-proteinases-1, -8, and -13 and of TIMP-1
  20. Inducibility of the Streptomyces traRts107-Ptra Expression Cassette in Mycobacterium smegmatis
  21. Shortest Known Prion Protein Allele in Highly BSE-Susceptible Lemurs
  22. Prostaglandin Deficiency Promotes Sensitization of Adenylyl Cyclase
https://doi.org/10.1515/BC.2000.061

Articles in the same Issue

  1. Highlight: GTP Binding Proteins Central Regulators in Cell Biology
  2. Signal Transduction and Post-Transcriptional Gene Expression
  3. Regulation of GTPases in the Bacterial Translation Machinery
  4. GTPase Mechanisms and Functions of Translation Factors on the Ribosome
  5. The Role of Heterotrimeric G Proteins in Platelet Activation
  6. Upstream and Downstream of Ran GTPase
  7. Nogo-A, a Potent Inhibitor of Neurite Outgrowth and Regeneration
  8. Rho GTPases as Targets of Bacterial Protein Toxins
  9. A Conserved Gβ Binding (GBB) Sequence Motif in Ste20p/PAK Family Protein Kinases
  10. Identification of a CpG Island in the Human LRP-2 Gene and Analysis of Its Methylation Status in Parathyroid Adenomas
  11. Theoretical Description of the Direct Exponential Amplification and Sequencing (DEXAS) Method
  12. Adenine Nucleotide N-Glycosidase Activity of the A-Chain of Cinnamomin Characterized by 1H-Nuclear Magnetic Resonance
  13. Msb4p, a Protein Involved in Cdc42p-Dependent Organization of the Actin Cytoskeleton, Is a Ypt/Rab-Specific GAP
  14. Muscle Phosphorylase Kinase Is Not a Substrate of AMP-Activated Protein Kinase
  15. Cationic Lipopolyamines Induce Degradation of PrPSc in Scrapie-Infected Mouse Neuroblastoma Cells
  16. Glycosylphosphatidylinositol-Specific Phospholipase D of Human Serum Activity Modulation by Naturally Occurring Amphiphiles
  17. Retrieval of the mrp2 Gene Encoded Conjugate Export Pump from the Canalicular Membrane Contributes to Cholestasis Induced by tert-Butyl Hydroperoxide and Chloro-Dinitrobenzene
  18. Matrix Metalloproteinases-2, -3, -7, -9 and -10, But Not MMP-11, Are Differentially Expressed in Normal, Benign Tumorigenic and Malignant Human Keratinocyte Cell Lines
  19. Human Keratinocyte Cell Lines Differ in the Expression of the Collagenolytic Matrix Metallo-proteinases-1, -8, and -13 and of TIMP-1
  20. Inducibility of the Streptomyces traRts107-Ptra Expression Cassette in Mycobacterium smegmatis
  21. Shortest Known Prion Protein Allele in Highly BSE-Susceptible Lemurs
  22. Prostaglandin Deficiency Promotes Sensitization of Adenylyl Cyclase
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