The disulfide isomerase Grp58 is a protective factor against prion neurotoxicity.

Prion diseases are transmissible neurodegenerative disorders characterized by extensive neuronal apoptosis and accumulation of misfolded prion protein (PrP(SC)). Recent reports indicate that PrP(SC) induces neuronal apoptosis via activation of the endoplasmic reticulum (ER) stress pathway and activation of the ER resident caspase-12. Here, we investigate the relationship between prion replication and induction of ER stress during different stages of the disease in a murine scrapie model.

Prion replication alters the distribution of synaptophysin and caveolin 1 in neuronal lipid rafts.

The main event in the pathogenesis of prion diseases is the conversion of the cellular prion protein (PrP(C)) into the abnormal, protease-resistant prion protein (PrP(res)). PrP(C) is a GPI-anchored protein located in lipid rafts or detergent-resistant membranes (DRMs). Here we describe the association of PrP with DRMs in neuronal cell bodies and axons during the course of murine scrapie and its relation with the distribution of the PrP-interacting proteins caveolin 1 and synaptophysin.

Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein.

Prion diseases are characterized by accumulation of misfolded prion protein (PrP(Sc)), and neuronal death by apoptosis. Here we show that nanomolar concentrations of purified PrP(Sc) from mouse scrapie brain induce apoptosis of N2A neuroblastoma cells. PrP(Sc) toxicity was associated with an increase of intracellular calcium released from endoplasmic reticulum (ER) and up-regulation of several ER chaperones.

Changes in the glycosylation pattern of prion protein in murine scrapie. Implications for the mechanism of neurodegeneration in prion diseases.

In prion diseases, the normal prion protein (PrP(c)) undergoes a conformational change that results in the abnormal form, named scrapie prion protein (PrP(sc)). The visual system of rodents provides a relatively simple neuronal model in which the cell bodies of neurons are confined to the retina and the axons constitute the optic nerve. We investigated by Western blot the profile of PrP(c) in the optic nerve and retina of normal hamsters and mice.