Prions Stress Out the ER

A conformational change in the prion protein (PrPC) results in the production of a neurotoxic form, PrPSc, which is implicated in transmissible spongiform encephalopathies. Hetz et al. determined that application of PrPSc to N2A neuroblastoma cells triggered apoptosis and activation of caspase-3, but not caspase-8 or caspase-1. PrPSc stimulated an increase in intracellular calcium concentration [Ca2+]i, resulting from release from the endoplasmic reticulum (ER)--increased [Ca2+]i was observed in the absence of extracellular calcium and was diminished by treatment of the cells with the ER calcium pump inhibitor thapsigargin. Application of PrPSc stimulated activation of the ER resident caspase-12 and increased expression of the ER chaperones, Grp94, Grp78, and Grp58, indicating that PrPSc triggered the ER stress response. The toxic effects of PrPSc or other triggers of ER stress were decreased in cells expressing a dominant-negative caspase-12 mutant. Although infection of N2A cells with prion protein (to endogenously express the PrPSc instead of exogenously applying the toxic protein) did not cause decreased cell viability under resting conditions, the infected cells were more sensitive to triggers of ER stress and showed decreased viability compared with uninfected cells. In mice infected with prion (139A-scrapie), active caspase-12 was detectable in the brain and regions of the brain with the highest caspase-12 activity also showed the most neuronal death. In addition, the brains of infected mice showed an increase in a subset of ER chaperones. Postmortem analysis of brain tissue from patients with Creutzfeldt-Jakob disease showed increased ER chaperones and active caspase-12, along with protease-resistant PrPSc. Thus, the ER stress response may play a critical role in the toxicity of prions, and the results suggest that this pathway may be a target for pharmacological intervention. C. Hetz, M. Russelakis-Carneiro, K. Maundrell, J. Castilla, C. Soto, Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. EMBO J.22, 5435-5445 (2003). [Abstract] [Full Text]