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Opposing effects of ERK and p38-JNK MAP kinase pathways on formation of prions in GT1-1 cells

Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

¹Correspondence: Department of Neuroscience, Retzius väg 8, Karolinska Institutet, Stockholm, SE-171 77 Sweden. E-mail: elin.nordstrom{at}ki.se

Brain-derived neurotrophic factor, which activates the extracellular regulated kinase (ERK) pathway, increases formation of prions in scrapie-infected gonadotropin-releasing hormone (GT1-1) cells. This indicates that conversion of the cellular prion protein PrP^C to its pathogenic isoform, PrP^Sc, can be regulated by physiological stimuli acting on specific signal transduction pathways. In the present study, we examined the involvement of different mitogen-activated protein (MAP) kinase cascades and the cAMP-PKA pathway in formation of proteinase K-resistant PrP^Sc (rPrP^Sc). Long-term depolarization of GT1-1 cells infected with the Rocky Mountain Laboratory strain of scrapie increased the formation of rPrP^Sc. This effect was associated to ERK activation and was blocked by the MAPK/ERK kinase (MEK) inhibitor U0126. Treatment with forskolin caused a similar increase in rPrP^Sc formation that was prevented by the protein kinase A (PKA) inhibitor H89. Both depolarization and forskolin treatment were accompanied by increased phosphorylation of the S6 ribosomal protein, while phosphorylation of histone H3 occurred only after forskolin treatment. Inhibitors of p38- and c-Jun NH₂-terminal kinase (JNK) promoted the formation of rPrP^Sc, in contrast to the clearance of rPrP^Sc produced by inhibitors of the ERK pathway. Thus, the ERK and the p38-JNK MAP kinase pathways appear to exert opposing effects on rPrP^Sc formation, suggesting that balances between these intracellular signaling cascades may regulate replication of prions.—Nordström, E., Fisone, G., Kristensson, K. Opposing effects of ERK and p38-JNK MAP kinase pathways on formation of prions in GT1-1 cells.

Key Words: scrapie • neuron • neurodegeneration • protein misfolding • PKA