Stress-protective signalling of prion protein is corrupted by scrapie prions.
Studies in transgenic mice revealed that neurodegeneration induced by scrapie prion (PrP(Sc)) propagation is dependent on neuronal expression of the cellular prion protein PrP(C). On the other hand, there is evidence that PrP(C) itself has a stress-protective activity. Here, we show that the toxic activity of PrP(Sc) and the protective activity of PrP(C) are interconnected. With a novel co-cultivation assay, we demonstrate that PrP(Sc) can induce apoptotic signalling in PrP(C)-expressing cells. However, cells expressing PrP mutants with an impaired stress-protective activity were resistant to PrP(Sc)-induced toxicity. We also show that the internal hydrophobic domain promotes dimer formation of PrP and that dimerization of PrP is linked to its stress-protective activity. PrP mutants defective in dimer formation did not confer enhanced stress tolerance. Moreover, in chronically scrapie-infected neuroblastoma cells the amount of PrP(C) dimers inversely correlated with the amount of PrP(Sc) and the resistance of the cells to various stress conditions. Our results provide new insight into the mechanism of PrP(C)-mediated neuroprotection and indicate that pathological PrP conformers abuse PrP(C)-dependent pathways for apoptotic signalling.
Department of Biochemistry, Neurobiochemistry, Ludwig-Maximilians-University Munich, München, Germany.
Angelika S
AS
Rambold
Veronika
V
Müller
Uri
U
Ron
Nir
N
Ben-Tal
Konstanze F
KF
Winklhofer
Jörg
J
Tatzelt
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D019281:Dimerization; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D018696:Neuroprotective Agents / Q000378:metabolism; D018621:PrPC Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction
D018696:Neuroprotective Agents; D018621:PrPC Proteins; D018620:PrPSc Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D048031:JNK Mitogen-Activated Protein Kinases