title: Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein.
abstract: 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. Caspase-12 activation was detected in cells treated with PrP(Sc), and cellular death was inhibited by overexpression of a catalytic mutant of caspase-12 or an ER-targeted Bcl-2 chimeric protein. Scrapie-infected N2A cells were more susceptible to ER-stress and to PrP(Sc) toxicity than non-infected cells. In scrapie-infected mice a correlation between caspase-12 activation and neuronal loss was observed in histological and biochemical analyses of different brain areas. The extent of prion replication was closely correlated with the up-regulation of ER-stress chaperone proteins. Similar results were observed in humans affected with sporadic and variant Creutzfeldt-Jakob disease, implicating for the first time the caspase-12 dependent pathway in a neurodegenerative disease in vivo, and thus offering novel potential targets for the treatment of prion disorders.
authors.affiliation: Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
authors.forename: Milene
authors.initials: M
authors.lastname: Russelakis-Carneiro
authors.forename: Kinsey
authors.initials: K
authors.lastname: Maundrell
authors.forename: Joaquin
authors.initials: J
authors.lastname: Castilla
authors.forename: Claudio
authors.initials: C
authors.lastname: Soto
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D053454:Caspase 12; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000473:pathology; D007562:Creutzfeldt-Jakob Syndrome / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000502:physiology* / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009447:Neuroblastoma; D018620:PrPSc Proteins / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D012608:Scrapie / Q000201:enzymology / Q000473:pathology*; D013314:Stress, Mechanical; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D018620:PrPSc Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C506444:CASP12 protein, human; C506440:Casp12 protein, mouse; D053454:Caspase 12; D020169:Caspases; D002118:Calcium