title: Protective effect of prion protein via the N-terminal region in mediating a protective effect on paraquat-induced oxidative injury in neuronal cells.
abstract: Transmissible spongiform encephalopathies are a group of neurodegenerative disorders caused by a posttranslational, conformational change in the cellular isoform of the prion protein (PrP(C)) into an infectious, disease-associated form (PrP(Sc)). Increasing evidence supports a role for PrP(C) in the cellular response to oxidative stress. We investigated the effect of oxidative stress mediated by paraquat exposure on SH-SY5Y neuroblastoma cells. A loss of mitochondrial membrane potential and subsequent reduction in ATP production were demonstrated in untransfected SH-SY5Y cells, an effect that was ameliorated by the expression of PrP(C). Cells expressing either PrP-DeltaOct, which lacks the octapeptide repeats, or PrP-DA, in which the N-terminus is tethered to the membrane, showed increased sensitivity to paraquat compared with cells expressing wild-type PrP(C) as shown by reduced viability, loss of their membrane integrity, and reduced mitochondrial bioenergetic measurements. Exposure of prion-infected mouse SMB15S cells to paraquat resulted in a reduction in viability to levels similar to those seen in the untransfected SH-SY5Y cells. However, "curing" the cells with pentosan sulfate restored the viability to the level observed in the SH-SY5Y cells expressing PrP(C). These data would indicate that the molecular mechanism promoting cellular resistance to oxidative stress had been compromised in the infected SMB15S cells, which could be reinstated upon curing. Our study supports the hypothesis that PrP(C) expression protects cells against paraquat-induced oxidative injury, demonstrates the significance of the N-terminal region of the protein in mediating this protective effect, and also shows that the biochemical consequences of prion infection may be reversed with therapeutic intervention.
authors: Department of Human Histology-CRPP, University of Liège, Sart Tilman, Liège, Belgium.
authors: Ingrid
authors: I
authors: Dupiereux
authors: Nandini
authors: N
authors: Falisse-Poirrier
authors: Willy
authors: W
authors: Zorzi
authors: Nicole T
authors: NT
authors: Watt
authors: Olivier
authors: O
authors: Thellin
authors: Danièle
authors: D
authors: Zorzi
authors: Olivier
authors: O
authors: Pierard
authors: Nigel M
authors: NM
authors: Hooper
authors: Ernst
authors: E
authors: Heinen
authors: Benaïssa
authors: B
authors: Elmoualij
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016877:Oxidants / Q000506:poisoning*; D018384:Oxidative Stress; D010269:Paraquat / Q000506:poisoning*; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology; D011328:Prions / Q000235:genetics / Q000494:pharmacology*; D020033:Protein Isoforms / Q000235:genetics / Q000494:pharmacology; D012608:Scrapie / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014162:Transfection
chemical_list: D018696:Neuroprotective Agents; D016877:Oxidants; D011328:Prions; D020033:Protein Isoforms; D010426:Pentosan Sulfuric Polyester; D000255:Adenosine Triphosphate; D010269:Paraquat