Home LiteratureArticle Details
PMID: 14532116 Published · ppublish English Journal Article

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

The EMBO journal ·Vol. 22 ·No. 20 ·2003-10-15 ·Pages 5435-45

Hetz C, Russelakis-Carneiro M, Maundrell K, Castilla J, Soto C

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.

MeSH Terms
Amino Acid Chloromethyl Ketones/pharmacology Animals Apoptosis/drug effects Calcium/metabolism Caspase 12 Caspase Inhibitors Caspases/metabolism Cell Survival/drug effects Cerebral Cortex/pathology Creutzfeldt-Jakob Syndrome/pathology Endoplasmic Reticulum/physiology,ultrastructure Enzyme Inhibitors/pharmacology Humans 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
Chemicals
Amino Acid Chloromethyl Ketones Caspase Inhibitors Enzyme Inhibitors PrPSc Proteins Proto-Oncogene Proteins c-bcl-2 Recombinant Proteins benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone CASP12 protein, human Casp12 protein, mouse Caspase 12 Caspases Calcium
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Hetz Claudio
Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
Russelakis-Carneiro Milene
Maundrell Kinsey
Castilla Joaquin
Soto Claudio
References (38)
38 references, click to expand
  1. In vitro replication of scrapie agent in a neuronal model: infection of PC12 cells.
    J Gen Virol. 1984 Dec;65 ( Pt 12):2191-8 PMID: 6439820
  2. Protein misfolding and disease: the case of prion disorders.
    Cell Mol Life Sci. 2003 Jan;60(1):133-43 PMID: 12613663
  3. Neurotoxicity of a prion protein fragment.
    Nature. 1993 Apr 8;362(6420):543-6 PMID: 8464494
  4. Erp61 is GRP58, a stress-inducible luminal endoplasmic reticulum protein, but is devoid of phosphatidylinositide-specific phospholipase C activity.
    Arch Biochem Biophys. 1994 Feb 1;308(2):454-60 PMID: 8109975
  5. Prion protein amyloidosis.
    Brain Pathol. 1996 Apr;6(2):127-45 PMID: 8737929
  6. Endoplasmic reticulum chaperones GRP78 and calreticulin prevent oxidative stress, Ca2+ disturbances, and cell death in renal epithelial cells.
    J Biol Chem. 1997 Aug 29;272(35):21751-9 PMID: 9268304
  7. A hypothalamic neuronal cell line persistently infected with scrapie prions exhibits apoptosis.
    J Virol. 1997 Nov;71(11):8821-31 PMID: 9343242
  8. Prion protein aggregation reverted by low temperature in transfected cells carrying a prion protein gene mutation.
    J Biol Chem. 1997 Nov 7;272(45):28461-70 PMID: 9353306
  9. Prions.
    Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83 PMID: 9811807
  10. Cell death in development.
    Cell. 1999 Jan 22;96(2):245-54 PMID: 9988219
  11. Proteasomal degradation and N-terminal protease resistance of the codon 145 mutant prion protein.
    J Biol Chem. 1999 Aug 13;274(33):23396-404 PMID: 10438517
  12. Biochemical pathways of caspase activation during apoptosis.
    Annu Rev Cell Dev Biol. 1999;15:269-90 PMID: 10611963
  13. Caspases find a new place to hide.
    Nature. 2000 Jan 6;403(6765):29-30 PMID: 10638735
  14. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta.
    Nature. 2000 Jan 6;403(6765):98-103 PMID: 10638761
  15. Caspase: executioner and undertaker of apoptosis.
    Int J Hematol. 1999 Dec;70(4):226-32 PMID: 10643147
  16. Reversion of prion protein conformational changes by synthetic beta-sheet breaker peptides.
    Lancet. 2000 Jan 15;355(9199):192-7 PMID: 10675119
  17. Cultured cell sublines highly susceptible to prion infection.
    J Virol. 2000 May;74(9):4377-86 PMID: 10756052
  18. The chaperone protein BiP binds to a mutant prion protein and mediates its degradation by the proteasome.
    J Biol Chem. 2000 Dec 8;275(49):38699-704 PMID: 10970892
  19. An endoplasmic reticulum-specific stress-activated caspase (caspase-12) is implicated in the apoptosis of A549 epithelial cells by respiratory syncytial virus.
    J Cell Biochem. 2001;80(3):441-54 PMID: 11135374
  20. Neurotoxicity but not infectivity of prion proteins can be induced reversibly in vitro.
    Arch Virol Suppl. 2000;(16):265-73 PMID: 11214930
  21. Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases.
    Neuron. 2001 Jan;29(1):15-32 PMID: 11182078
  22. Apoptosis in neurodegenerative disorders.
    Nat Rev Mol Cell Biol. 2000 Nov;1(2):120-9 PMID: 11253364
  23. The metabolism and imaging in live cells of the bovine prion protein in its native form or carrying single amino acid substitutions.
    Mol Cell Neurosci. 2001 Mar;17(3):521-38 PMID: 11273647
  24. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding.
    Nature. 2001 Jun 14;411(6839):810-3 PMID: 11459061
  25. Coupling endoplasmic reticulum stress to the cell death program. Mechanism of caspase activation.
    J Biol Chem. 2001 Sep 7;276(36):33869-74 PMID: 11448953
  26. Prion protein fragment PrP-(106-126) induces apoptosis via mitochondrial disruption in human neuronal SH-SY5Y cells.
    J Biol Chem. 2001 Nov 23;276(47):43516-23 PMID: 11533027
  27. Transient expression of wild-type or mitochondrially targeted Bcl-2 induces apoptosis, whereas transient expression of endoplasmic reticulum-targeted Bcl-2 is protective against Bax-induced cell death.
    J Biol Chem. 2001 Nov 23;276(47):44117-28 PMID: 11546793
  28. Wild-type, mitochondrial and ER-restricted Bcl-2 inhibit DNA damage-induced apoptosis but do not affect death receptor-induced apoptosis.
    J Cell Sci. 2001 Dec;114(Pt 23):4161-72 PMID: 11739649
  29. Microcin E492, a channel-forming bacteriocin from Klebsiella pneumoniae, induces apoptosis in some human cell lines.
    Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2696-701 PMID: 11880624
  30. Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation.
    Hum Mol Genet. 2002 Jun 15;11(13):1505-15 PMID: 12045204
  31. Human caspase 12 has acquired deleterious mutations.
    Biochem Biophys Res Commun. 2002 May 3;293(2):722-6 PMID: 12054529
  32. Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsic pathway.
    J Biol Chem. 2002 Jun 14;277(24):21836-42 PMID: 11919205
  33. Apoptosis-based therapies.
    Nat Rev Drug Discov. 2002 Feb;1(2):111-21 PMID: 12120092
  34. Stimulation of PrP(C) retrograde transport toward the endoplasmic reticulum increases accumulation of PrP(Sc) in prion-infected cells.
    J Biol Chem. 2002 Oct 11;277(41):38972-7 PMID: 12163492
  35. Caspase-dependent initiation of apoptosis and necrosis by the Fas receptor in lymphoid cells: onset of necrosis is associated with delayed ceramide increase.
    J Cell Sci. 2002 Dec 1;115(Pt 23):4671-83 PMID: 12415011
  36. Overexpressed protein disulfide isomerase in brains of patients with sporadic Creutzfeldt-Jakob disease.
    Neurosci Lett. 2002 Dec 16;334(3):196-200 PMID: 12453628
  37. Unfolding the role of protein misfolding in neurodegenerative diseases.
    Nat Rev Neurosci. 2003 Jan;4(1):49-60 PMID: 12511861
  38. Scrapie-infected murine neuroblastoma cells produce protease-resistant prion proteins.
    J Virol. 1988 May;62(5):1558-64 PMID: 3282080
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdg537
Published
2003-10-15
Pages
5435-45
Language
English
Region
England
NLM ID
8208664
PMCID
PMC213791
Subset
IM
Corrections
ErratumIn
PMID: 34523135
External Links
PubMed source DOI: 10.1093/emboj/cdg537 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2