ER stress signaling and neurodegeneration: At the intersection between Alzheimer's disease and Prion-related disorders

Virus Research

Volumn 207, Issue , 2015, Pages 69-75

  Torres, Mauricio ^a,b,c   Matamala, José Manuel ^a,b   Duran Aniotz, Claudia ^a,b   Cornejo, Victor Hugo ^a,b   Foley, Andrew ^a,b   Hetz, Claudio ^a,b,d,e  

^a UNIVERSITY OF CHILE   (Chile)

^b UNIVERSITY OF CHILE   (Chile)

^c UNIVERSIDAD DE MAGALLANES   (Chile)

^d Millennium Nucleus for Regenerative Biology and Neurounion Biomedical Foundation   (Chile)

^e HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

Author keywords

Amyloid formation; ER stress; Prion like diseases; Sustained translational repression; Targeting ER stress; Unfolded protein response (UPR)

Indexed keywords

AMYLOID; CENTRAL NERVOUS SYSTEM AGENTS; PRION PROTEIN; PRION; PROTEIN;

ALZHEIMER DISEASE; ARTICLE; COGNITIVE DEFECT; DRUG TARGETING; ENDOPLASMIC RETICULUM STRESS; HUMAN; NEUROPATHOLOGY; NONHUMAN; PRION DISEASE; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN HOMEOSTASIS; PROTEIN MISFOLDING; PROTEIN STRUCTURE; SECRETORY PATHWAY; SIGNAL TRANSDUCTION; UNFOLDED PROTEIN RESPONSE; ANIMAL; CHEMISTRY; METABOLISM; NERVE DEGENERATION; PATHOPHYSIOLOGY; PRION; PROTEIN FOLDING;

ALZHEIMER DISEASE; ANIMALS; ENDOPLASMIC RETICULUM STRESS; HUMANS; NERVE DEGENERATION; PRIONS; PROTEIN FOLDING; PROTEINS;

EID: 84938744930     PISSN: 01681702     EISSN: 18727492     Source Type: Journal    
DOI: 10.1016/j.virusres.2014.12.018     Document Type: Article

References (91)

1. Acosta-Alvear D., Zhou Y., Blais A., Tsikitis M., Lents N.H., Arias C., Lennon C.J., Kluger Y., Dynlacht B.D. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol. Cell 2007, 27(1):53-66.
2. Aguzzi A., Sigurdson C., Heikenwaelder M. Molecular mechanisms of prion pathogenesis. Annu. Rev. Pathol. 2008, 3:11-40.
3. Axten J.M., Medina J.R., Feng Y., Shu A., Romeril S.P., Grant S.W., Li W.H., Heerding D.A., Minthorn E., Mencken T., Atkins C., Liu Q., Rabindran S., Kumar R., Hong X., Goetz A., Stanley T., Taylor J.D., Sigethy S.D., Tomberlin G.H., Hassell A.M., Kahler K.M., Shewchuk L.M., Gampe R.T. Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J. Med. Chem. 2012, 55(16):7193-7207.
4. Bertram L., Tanzi R.E. Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses. Nat. Rev. Neurosci. 2008, 9(10):768-778.
5. Bezprozvanny I., Mattson M.P. Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci. 2008, 31(9):454-463.
6. Blake C.C., Serpell L.C., Sunde M., Sandgren O., Lundgren E. A molecular model of the amyloid fibril. Ciba Found. Symp. 1996, 199:6-15. discussion 15-21, 40-6.
7. Boyce M., Bryant K.F., Jousse C., Long K., Harding H.P., Scheuner D., Kaufman R.J., Ma D., Coen D.M., Ron D., Yuan J. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 2005, 307(5711):935-939.
8. Braak H., Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 1991, 82(4):239-259.
9. Brown A.R., Rebus S., McKimmie C.S., Robertson K., Williams A., Fazakerley J.K. Gene expression profiling of the preclinical scrapie-infected hippocampus. Biochem. Biophys. Res. Commun. 2005, 334(1):86-95.
10. Casas-Tinto S., Zhang Y., Sanchez-Garcia J., Gomez-Velazquez M., Rincon-Limas D.E., Fernandez-Funez P. The ER stress factor XBP1s prevents amyloid-beta neurotoxicity. Hum. Mol. Genet. 2011, 20(11):2144-2160.
11. Castilla J., Saa P., Hetz C., Soto C. In vitro generation of infectious scrapie prions. Cell 2005, 121(2):195-206.
12. Chiti F., Dobson C.M. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 2006, 75:333-366.
13. Colby D.W., Prusiner S.B. De novo generation of prion strains. Nat. Rev. Microbiol. 2011, 9(11):771-777.
14. Collinge J. Prion diseases of humans and animals: their causes and molecular basis. Annu. Rev. Neurosci. 2001, 24:519-550.
15. Come J.H., Fraser P.E., Lansbury P.T. A kinetic model for amyloid formation in the prion diseases: importance of seeding. Proc. Natl. Acad. Sci. U. S. A. 1993, 90(13):5959-5963.
16. Cornejo V.H., Hetz C. The unfolded protein response in Alzheimer's disease. Semin. Immunopathol. 2013, 35(3):277-292.
17. Costa-Mattioli M., Gobert D., Harding H., Herdy B., Azzi M., Bruno M., Bidinosti M., Ben Mamou C., Marcinkiewicz E., Yoshida M., Imataka H., Cuello A.C., Seidah N., Sossin W., Lacaille J.C., Ron D., Nader K., Sonenberg N. Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature 2005, 436(7054):1166-1173.
18. Costa-Mattioli M., Gobert D., Stern E., Gamache K., Colina R., Cuello C., Sossin W., Kaufman R., Pelletier J., Rosenblum K., Krnjevic K., Lacaille J.C., Nader K., Sonenberg N. eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell 2007, 129(1):195-206.
19. Costa-Mattioli M., Sossin W.S., Klann E., Sonenberg N. Translational control of long-lasting synaptic plasticity and memory. Neuron 2009, 61(1):10-26.
20. Cuanalo-Contreras K., Mukherjee A., Soto C. Role of protein misfolding and proteostasis deficiency in protein misfolding diseases and aging. Int. J. Cell Biol. 2013, 2013:638083.
21. de Calignon A., Polydoro M., Suarez-Calvet M., William C., Adamowicz D.H., Kopeikina K.J., Pitstick R., Sahara N., Ashe K.H., Carlson G.A., Spires-Jones T.L., Hyman B.T. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 2012, 73(4):685-697.
22. Dery M.A., Jodoin J., Ursini-Siegel J., Aleynikova O., Ferrario C., Hassan S., Basik M., LeBlanc A.C. Endoplasmic reticulum stress induces PRNP prion protein gene expression in breast cancer. Breast Cancer Res. 2013, 15(2):R22.
23. Dobson C.M. Getting out of shape. Nature 2002, 418(6899):729-730.
24. Douglas P.M., Dillin A. Protein homeostasis and aging in neurodegeneration. J. Cell Biol. 2010, 190(5):719-729.
25. Eisele Y.S., Obermuller U., Heilbronner G., Baumann F., Kaeser S.A., Wolburg H., Walker L.C., Staufenbiel M., Heikenwalder M., Jucker M. Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science 2010, 330(6006):980-982.
26. Ferreiro E., Costa R., Marques S., Cardoso S.M., Oliveira C.R., Pereira C.M. Involvement of mitochondria in endoplasmic reticulum stress-induced apoptotic cell death pathway triggered by the prion peptide PrP(106-126). J. Neurochem. 2008, 104(3):766-776.
27. Ferreiro E., Oliveira C.R., Pereira C.M. The release of calcium from the endoplasmic reticulum induced by amyloid-beta and prion peptides activates the mitochondrial apoptotic pathway. Neurobiol. Dis. 2008, 30(3):331-342.
28. Ferreiro E., Resende R., Costa R., Oliveira C.R., Pereira C.M. An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity. Neurobiol. Dis. 2006, 23(3):669-678.
29. Finkel T. Radical medicine: treating ageing to cure disease. Nat. Rev. Mol. Cell Biol. 2005, 6(12):971-976.
30. Halliday M., Mallucci G.R. Targeting the unfolded protein response in neurodegeneration: a new approach to therapy. Neuropharmacology 2014, 76(Pt A):169-174.
31. Hardy J., Selkoe D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002, 297(5580):353-356.
32. Hetz C., Castilla J., Soto C. Perturbation of endoplasmic reticulum homeostasis facilitates prion replication. J. Biol. Chem. 2007, 282(17):12725-12733.
33. Hetz C., Chevet E., Harding H.P. Targeting the unfolded protein response in disease. Nat. Rev. Drug Discov. 2013, 12(9):703-719.
34. Hetz C., Lee A.H., Gonzalez-Romero D., Thielen P., Castilla J., Soto C., Glimcher L.H. Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis. Proc. Natl. Acad. Sci. U. S. A. 2008, 105(2):757-762.
35. Hetz C., Mollereau B. Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat. Rev. Neurosci. 2014, 15(4):233-249.
36. Hetz C., Russelakis-Carneiro M., Maundrell K., Castilla J., Soto C. Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. EMBO J. 2003, 22(20):5435-5445.
37. Hetz C., Russelakis-Carneiro M., Walchli S., Carboni S., Vial-Knecht E., Maundrell K., Castilla J., Soto C. The disulfide isomerase Grp58 is a protective factor against prion neurotoxicity. J. Neurosci. 2005, 25(11):2793-2802.
38. Hetz C., Thielen P., Matus S., Nassif M., Court F., Kiffin R., Martinez G., Cuervo A.M., Brown R.H., Glimcher L.H. XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev. 2009, 23(19):2294-2306.
39. Hetz C.A., Soto C. Stressing out the ER: a role of the unfolded protein response in prion-related disorders. Curr. Mol. Med. 2006, 6(1):37-43.
40. Hollien J., Lin J.H., Li H., Stevens N., Walter P., Weissman J.S. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J. Cell Biol. 2009, 186(3):323-331.
41. Jarrett J.T., Lansbury P.T. Seeding one-dimensional crystallization of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie?. Cell 1993, 73(6):1055-1058.
42. Jiang Z., Belforte J.E., Lu Y., Yabe Y., Pickel J., Smith C.B., Je H.S., Lu B., Nakazawa K. eIF2alpha phosphorylation-dependent translation in CA1 pyramidal cells impairs hippocampal memory consolidation without affecting general translation. J. Neurosci. 2010, 30(7):2582-2594.
43. Kakiuchi C., Iwamoto K., Ishiwata M., Bundo M., Kasahara T., Kusumi I., Tsujita T., Okazaki Y., Nanko S., Kunugi H., Sasaki T., Kato T. Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nat. Genet. 2003, 35(2):171-175.
44. Kane M.D., Lipinski W.J., Callahan M.J., Bian F., Durham R.A., Schwarz R.D., Roher A.E., Walker L.C. Evidence for seeding of beta-amyloid by intracerebral infusion of Alzheimer brain extracts in beta-amyloid precursor protein-transgenic mice. J. Neurosci. 2000, 20(10):3606-3611.
45. Karran E., Mercken M., De Strooper B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov. 2011, 10(9):698-712.
46. Langer F., Eisele Y.S., Fritschi S.K., Staufenbiel M., Walker L.C., Jucker M. Soluble Abeta seeds are potent inducers of cerebral beta-amyloid deposition. J. Neurosci. 2011, 31(41):14488-14495.
47. Lee A.H., Iwakoshi N.N., Glimcher L.H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell. Biol. 2003, 23(21):7448-7459.
48. Liu S.Y., Wang W., Cai Z.Y., Yao L.F., Chen Z.W., Wang C.Y., Zhao B., Li K.S. Polymorphism-116C/G of human X-box-binding protein 1 promoter is associated with risk of Alzheimer's disease. CNS Neurosci. Ther. 2013, 19(4):229-234.
49. Loewen C.A., Feany M.B. The unfolded protein response protects from tau neurotoxicity in vivo. PLoS ONE 2010, 5.(9).
50. Ma T., Trinh M.A., Wexler A.J., Bourbon C., Gatti E., Pierre P., Cavener D.R., Klann E. Suppression of eIF2alpha kinases alleviates Alzheimer's disease-related plasticity and memory deficits. Nat. Neurosci. 2013, 16(9):1299-1305.
51. Maly D.J., Papa F.R. Druggable sensors of the unfolded protein response. Nat. Chem. Biol. 2014, 10(11):892-901.
52. Meyer-Luehmann M., Coomaraswamy J., Bolmont T., Kaeser S., Schaefer C., Kilger E., Neuenschwander A., Abramowski D., Frey P., Jaton A.L., Vigouret J.M., Paganetti P., Walsh D.M., Mathews P.M., Ghiso J., Staufenbiel M., Walker L.C., Jucker M. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 2006, 313(5794):1781-1784.
53. Morales R., Duran-Aniotz C., Castilla J., Estrada L.D., Soto C. De novo induction of amyloid-beta deposition in vivo. Mol. Psychiatry 2011, 17(12):1347-1353.
54. Moreno J.A., Halliday M., Molloy C., Radford H., Verity N., Axten J.M., Ortori C.A., Willis A.E., Fischer P.M., Barrett D.A., Mallucci G.R. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci. Transl. Med. 2013, 5(206):206ra138.
55. Moreno J.A., Radford H., Peretti D., Steinert J.R., Verity N., Martin M.G., Halliday M., Morgan J., Dinsdale D., Ortori C.A., Barrett D.A., Tsaytler P., Bertolotti A., Willis A.E., Bushell M., Mallucci G.R. Sustained translational repression by eIF2alpha-P mediates prion neurodegeneration. Nature 2012, 485(7399):507-511.
56. Mukherjee A., Morales-Scheihing D., Gonzalez-Romero D., Green K., Taglialatela G., Soto C. Calcineurin inhibition at the clinical phase of prion disease reduces neurodegeneration, improves behavioral alterations and increases animal survival. PLoS Pathog. 2010, 6(10):e1001138.
57. O'Connor T., Sadleir K.R., Maus E., Velliquette R.A., Zhao J., Cole S.L., Eimer W.A., Hitt B., Bembinster L.A., Lammich S., Lichtenthaler S.F., Hebert S.S., De Strooper B., Haass C., Bennett D.A., Vassar R. Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron 2008, 60(6):988-1009.
58. Parchi P., Giese A., Capellari S., Brown P., Schulz-Schaeffer W., Windl O., Zerr I., Budka H., Kopp N., Piccardo P., Poser S., Rojiani A., Streichemberger N., Julien J., Vital C., Ghetti B., Gambetti P., Kretzschmar H. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann. Neurol. 1999, 46(2):224-233.
59. Pauwels K., Gijsbers R., Toelen J., Schambach A., Willard-Gallo K., Verheust C., Debyser Z., Herman P. State-of-the-art lentiviral vectors for research use: risk assessment and biosafety recommendations. Curr. Gene Ther. 2009, 9(6):459-474.
60. Price D.L., Sisodia S.S., Borchelt D.R. Genetic neurodegenerative diseases: the human illness and transgenic models. Science 1998, 282(5391):1079-1083.
61. Prusiner S.B. Novel proteinaceous infectious particles cause scrapie. Science 1982, 216(4542):136-144.
62. Prusiner S.B. Prions. Proc. Natl. Acad. Sci. U. S. A. 1998, 95(23):13363-13383.
63. Quaglio E., Restelli E., Garofoli A., Dossena S., De Luigi A., Tagliavacca L., Imperiale D., Migheli A., Salmona M., Sitia R., Forloni G., Chiesa R. Expression of mutant or cytosolic PrP in transgenic mice and cells is not associated with endoplasmic reticulum stress or proteasome dysfunction. PLoS ONE 2011, 6(4):e19339.
64. Rane N.S., Kang S.W., Chakrabarti O., Feigenbaum L., Hegde R.S. Reduced translocation of nascent prion protein during ER stress contributes to neurodegeneration. Dev. Cell 2008, 15(3):359-370.
65. Ron D., Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 2007, 8(7):519-529.
66. Saborio G.P., Permanne B., Soto C. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 2001, 411(6839):810-813.
67. Safra M., Ben-Hamo S., Kenyon C., Henis-Korenblit S. The ire-1 ER stress-response pathway is required for normal secretory-protein metabolism in C. elegans. J. Cell Sci. 2013, 126(Pt 18):4136-4146.
68. Salvadores N., Shahnawaz M., Scarpini E., Tagliavini F., Soto C. Detection of misfolded Abeta oligomers for sensitive biochemical diagnosis of Alzheimer's disease. Cell Rep. 2014, 7(1):261-268.
69. Sanders D.W., Kaufman S.K., DeVos S.L., Sharma A.M., Mirbaha H., Li A., Barker S.J., Foley A.C., Thorpe J.R., Serpell L.C., Miller T.M., Grinberg L.T., Seeley W.W., Diamond M.I. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 2014, 82(6):1271-1288.
70. Selkoe D.J. Alzheimer's disease: genes, proteins, and therapy. Physiol. Rev. 2001, 81(2):741-766.
71. Selkoe D.J. Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases. Nat. Cell Biol. 2004, 6(11):1054-1061.
72. Shoulders M.D., Ryno L.M., Genereux J.C., Moresco J.J., Tu P.G., Wu C., Yates J.R., Su A.I., Kelly J.W., Wiseman R.L. Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep. 2013, 3(4):1279-1292.
73. Sidrauski C., Acosta-Alvear D., Khoutorsky A., Vedantham P., Hearn B.R., Li H., Gamache K., Gallagher C.M., Ang K.K., Wilson C., Okreglak V., Ashkenazi A., Hann B., Nader K., Arkin M.R., Renslo A.R., Sonenberg N., Walter P. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife 2013, 2:e00498.
74. Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat. Rev. Neurosci. 2003, 4(1):49-60.
75. Soto C. Transmissible proteins: expanding the prion heresy. Cell 2012, 149(5):968-977.
76. Soto C., Anderes L., Suardi S., Cardone F., Castilla J., Frossard M.J., Peano S., Saa P., Limido L., Carbonatto M., Ironside J., Torres J.M., Pocchiari M., Tagliavini F. Pre-symptomatic detection of prions by cyclic amplification of protein misfolding. FEBS Lett. 2005, 579(3):638-642.
77. Soto C., Estrada L., Castilla J. Amyloids, prions and the inherent infectious nature of misfolded protein aggregates. Trends Biochem. Sci. 2006, 31(3):150-155.
78. Steele A.D., Hetz C., Yi C.H., Jackson W.S., Borkowski A.W., Yuan J., Wollmann R.H., Lindquist S. Prion pathogenesis is independent of caspase-12. Prion 2007, 1(4):243-247.
79. Torres M., Castillo K., Armisen R., Stutzin A., Soto C., Hetz C. Prion protein misfolding affects calcium homeostasis and sensitizes cells to endoplasmic reticulum stress. PLoS ONE 2010, 5(12):e15658.
80. Urano F., Wang X., Bertolotti A., Zhang Y., Chung P., Harding H.P., Ron D. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000, 287(5453):664-666.
81. Urra H., Dufey E., Lisbona F., Rojas-Rivera D., Hetz C. When ER stress reaches a dead end. Biochim. Biophys. Acta 2013, 1833(12):3507-3517.
82. Vidal R.L., Figueroa A., Court F.A., Thielen P., Molina C., Wirth C., Caballero B., Kiffin R., Segura-Aguilar J., Cuervo A.M., Glimcher L.H., Hetz C. Targeting the UPR transcription factor XBP1 protects against Huntington's disease through the regulation of FoxO1 and autophagy. Hum. Mol. Genet. 2012, 21(10):2245-2262.
83. Walker L.C., Callahan M.J., Bian F., Durham R.A., Roher A.E., Lipinski W.J. Exogenous induction of cerebral beta-amyloidosis in betaAPP-transgenic mice. Peptides 2002, 23(7):1241-1247.
84. Walsh D.M., Selkoe D.J. Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration. Protein Pept. Lett. 2004, 11(3):213-228.
85. Walter P., Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011, 334(6059):1081-1086.
86. Watts J.C., Condello C., Stohr J., Oehler A., Lee J., DeArmond S.J., Lannfelt L., Ingelsson M., Giles K., Prusiner S.B. Serial propagation of distinct strains of Abeta prions from Alzheimer's disease patients. Proc. Natl. Acad. Sci. U. S. A. 2014.
87. Xu K., Zhu X.P. Endoplasmic reticulum stress and prion diseases. Rev. Neurosci. 2012, 23(1):79-84.
88. Yoo B.C., Krapfenbauer K., Cairns N., Belay G., Bajo M., Lubec G. Overexpressed protein disulfide isomerase in brains of patients with sporadic Creutzfeldt-Jakob disease. Neurosci. Lett. 2002, 334(3):196-200.
89. Yoon S.O., Park D.J., Ryu J.C., Ozer H.G., Tep C., Shin Y.J., Lim T.H., Pastorino L., Kunwar A.J., Walton J.C., Nagahara A.H., Lu K.P., Nelson R.J., Tuszynski M.H., Huang K. JNK3 perpetuates metabolic stress induced by Abeta peptides. Neuron 2012, 75(5):824-837.
90. Zhang P., McGrath B., Li S., Frank A., Zambito F., Reinert J., Gannon M., Ma K., McNaughton K., Cavener D.R. The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol. Cell. Biol. 2002, 22(11):3864-3874.
91. Zhu P.J., Huang W., Kalikulov D., Yoo J.W., Placzek A.N., Stoica L., Zhou H., Bell J.C., Friedlander M.J., Krnjevic K., Noebels J.L., Costa-Mattioli M. Suppression of PKR promotes network excitability and enhanced cognition by interferon-gamma-mediated disinhibition. Cell 2011, 147(6):1384-1396.