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22 (20): 5435-5445

Copyright © 2003 by the European Molecular Biology Organization.

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

Claudio Hetz1,2, Milene Russelakis-Carneiro1, Kinsey Maundrell1, Joaquin Castilla1,3, and Claudio Soto1,3,4

1 Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland, 2 Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, Chile and 3 Department of Neurology, University of Texas Medical Branch, Galveston, Texas, TX, USA 4 Corresponding author e-mail: clsoto{at}utmb.edu

Abstract: 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.

Key Words: Keywords: apoptosis/caspase-12/Creutzfeldt–Jakob disease/ER-stress/PrPSc/scrapie

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Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882