Resistance of cell lines to prion toxicity aided by phospho-ERK expression.
Prion diseases are fatal neurodegenerative disorders. They are characterised by neuronal loss and the accumulation of an abnormal protein in the CNS. Cell lines exist that express the toxic form of the prion protein (PrP) with little evidence of cell death. Other cell based models studying the mechanism by which cell death occurs employ exogenous application of peptides or fragments of PrP. In this study, we demonstrated that full-length recombinant PrP binding manganese was toxic to PrP-expressing cell lines and primary neuronal cultures but not to PrP-knockout neurones. This toxic form of PrP was also toxic to cell lines equivalently regardless of whether they were infected with scrapie or not. Both scrapie-infected cells and cells resistant to the toxicity of PrP showed increased levels of phosphorylated ERK protein. Scrapie-infected cells also showed elevated levels of caspase 12. Inhibition of phospho-ERK resulted in increased cell death suggesting the increased levels of phospho-ERK served a protective effect. These results suggest that scrapie-infected cell lines resist the toxicity of the prions they generate because they produce only low levels of abnormal protein and have increased resistance to apoptotic signs because of heightened activity of the MAP kinase pathway.
Uppington
Kay M
KM
Department of Biology and Biochemistry, University of Bath, Bath, UK.
Brown
David R
DR
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics*; D053454:Caspase 12 / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D019610:Cytoprotection / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics; D008345:Manganese / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010766:Phosphorylation; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism*; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D011328:Prions / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D017510:Protein Folding; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D012608:Scrapie / Q000235:genetics / Q000378:metabolism
D018620:PrPSc Proteins; D011328:Prions; D011994:Recombinant Proteins; D008345:Manganese; D048049:Extracellular Signal-Regulated MAP Kinases; D053454:Caspase 12