Stress-protective signalling of prion protein is corrupted by scrapie prions.

Studies in transgenic mice revealed that neurodegeneration induced by scrapie prion (PrPSc) propagation is dependent on neuronal expression of the cellular prion protein PrPC. On the other hand, there is evidence that PrPC itself has a stress-protective activity. Here, we show that the toxic activity of PrPSc and the protective activity of PrPC are interconnected. With a novel co-cultivation assay, we demonstrate that PrPSc can induce apoptotic signalling in PrPC-expressing cells. However, cells expressing PrP mutants with an impaired stress-protective activity were resistant to PrPSc-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 PrPC dimers inversely correlated with the amount of PrPSc and the resistance of the cells to various stress conditions. Our results provide new insight into the mechanism of PrPC-mediated neuroprotection and indicate that pathological PrP conformers abuse PrPC-dependent pathways for apoptotic signalling.