NR APHX
AU Hetz,C.A.; Russelakis-Carneiro,M.; Maundrell,K.; Castilla,J.; Soto,C.
TI Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein
QU EMBO Journal 2003 Oct 15; 22(20): 5435-45
PT journal article
AB Prion diseases are characterized by accumulation of misfolded prion protein (PrPsc), and neuronal death by apoptosis. Here we show that nanomolar concentrations of purified PrPsc from mouse scrapie brain induce apoptosis of N2A neuroblastoma cells. PrPsc 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 PrPsc, 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 PrPsc 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.
MH Amino Acid Chloromethyl Ketones/pharmacology; Animals; Apoptosis/drug effects; Calcium/metabolism; Caspases/antagonists & inhibitors/*metabolism; Cell Survival/drug effects; Cerebral Cortex/pathology; Creutzfeldt-Jakob Syndrome/pathology; Endoplasmic Reticulum/*physiology/ultrastructure; Enzyme Inhibitors/pharmacology; Human; Mice; Mice, Inbred C57BL; Neuroblastoma; PrPsc Proteins/*toxicity; Proto-Oncogene Proteins c-bcl-2/genetics; Recombinant Proteins/metabolism; Scrapie/enzymology/*pathology; Stress, Mechanical; Transfection; Tumor Cells, Cultured
AD Claudio Hetz, Milene Russelakis-Carneiro, Kinsey Maundrell, Joaquin Castilla, Claudio Soto, Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland; Claudio Hetz, Instituto de Ciencias Biomedicas, Universidad de Chile, Santiago, Chile; Joaquin Castilla, Claudio Soto, Department of Neurology, University of Texas Medical Branch, Galveston, Texas, TX, USA; Corresponding author is Claudio Soto, e-mail: clsoto@utmb.edu
SP englisch
PO England