title: The disulfide isomerase Grp58 is a protective factor against prion neurotoxicity.
abstract: 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. The first alteration observed consists of the upregulation of the ER chaperone of the glucose-regulated protein Grp58, which was detected during the presymptomatic phase and followed closely the formation of PrP(SC). An increase in Grp58 expression correlated with PrP(SC) accumulation at all stages of the disease in different brain areas, suggesting that this chaperone may play an important role in the cellular response to prion infection. Indeed, in vitro studies using N2a neuroblastoma cells demonstrated that inhibition of Grp58 expression with small interfering RNA led to a significant enhancement of PrP(SC) toxicity. Conversely, overexpression of Grp58 protected cells against PrP(SC) toxicity and decreased the rate of caspase-12 activation. Grp58 and PrP were shown to interact by coimmunoprecipitation, observing a higher interaction in cells infected with scrapie prions. Our data indicate that expression of Grp58 is an early cellular response to prion replication, acting as a neuroprotective factor against prion neurotoxicity. Our findings suggest that targeting Grp58 interaction may have applications for developing novel strategies for treatment and early diagnosis of prion diseases.
authors.affiliation: Serono Pharmaceutical Research Institute, 1228 Plan-les-Ouates, Geneva, Switzerland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
authors.forename: Milene
authors.initials: M
authors.lastname: Russelakis-Carneiro
authors.forename: Sébastien
authors.initials: S
authors.lastname: Wälchli
authors.forename: Sonia
authors.initials: S
authors.lastname: Carboni
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Vial-Knecht
authors.forename: Kinsey
authors.initials: K
authors.lastname: Maundrell
authors.forename: Joaquín
authors.initials: J
authors.lastname: Castilla
authors.forename: Claudio
authors.initials: C
authors.lastname: Soto
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000001:Calcimycin / Q000494:pharmacology; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology; D002277:Carcinoma; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D017096:Prion Diseases / Q000209:etiology* / Q000517:prevention & control*; D011328:Prions / Q000378:metabolism / Q000472:pathogenicity*; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D000900:Anti-Bacterial Agents; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D011328:Prions; D034741:RNA, Small Interfering; C018551:glucose-regulated proteins; D000001:Calcimycin; D010751:Phosphopyruvate Hydratase; C513195:Pdia3 protein, mouse; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human