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Prions Stress Out the ER

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Science  31 Oct 2003:
Vol. 302, Issue 5646, pp. 749
DOI: 10.1126/science.302.5646.749c

A conformational change in the normal form of the prion protein (PrPC) yields the neurotoxic form PrPSc, which is implicated in transmissible spongiform encephalopathies. Hetz et al. determined that application of PrPSc to N2A neuroblastoma cells initiated an increase in intracellular calcium concentration, because of release from the endoplasmic reticulum (ER). Application of PrPSc also activated the ER-resident caspase-12, one of a family of proteases that mediate programmed cell death, and increased expression of the ER chaperones, consistent with induction of the ER stress response. In mice infected with prion (139A-scrapie), active caspase-12 was detected in the brain, and regions of the brain with the highest caspase-12 activity showed the most neuronal death. Postmortem analysis of brain tissue from several patients with Creutzfeldt-Jakob disease revealed the presence of ER chaperones and active caspase-12. Thus, the ER stress response may play a critical role in the toxicity of prions. — NG

EMBO J. 22, 5435 (2003).

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