Fig. 8. A working hypothesis for PrP^Sc-induced apoptosis in neuronal cells. Interaction of PrP^Sc with an unknown receptor protein activates a signaling pathway, which induces the release of calcium from the ER and ER-stress, as evidenced by the up-regulation of ER chaperones (i.e. Grp58, Grp78 and/or Grp94). ER-stress leads to activation of caspase 12, which in turn cleaves and activates the executioner caspase-3, leading to apoptosis.