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Integrated Stress Response in Neuronal Pathology and in Health

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Abstract

Neurodegeneration involves progressive pathological loss of a specific population of neurons, glial activation, and dysfunction of myelinating oligodendrocytes leading to cognitive impairment and altered movement, breathing, and senses. Neuronal degeneration is a hallmark of aging, stroke, drug abuse, toxic chemical exposure, viral infection, chronic inflammation, and a variety of neurological diseases. Accumulation of intra- and extracellular protein aggregates is a common characteristic of cell pathologies. Excessive production of reactive oxygen species and nitric oxide, induction of endoplasmic reticulum stress, and accumulation of misfolded protein aggregates have been shown to trigger a defensive mechanism called integrated stress response (ISR). Activation of ISR is important for synaptic plasticity in learning and memory formation. However, sustaining of ISR may lead to the development of neuronal pathologies and altered patterns in behavior and perception.

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Abbreviations

AD:

Alzheimer’s disease

ALS:

amyotrophic lateral sclerosis

ATF4:

cAMP element binding transcription factors 4

BiP:

binding immunoglobulin protein or 78-kDa glucose regulated protein

CHOP:

growth arrest and DNA damage-inducible/C/EBP homologous protein (also GADD153)

eIF:

translation initiation factor

ER:

endoplasmic reticulum

FTD:

frontotemporal dementia

GADD34:

growth arrest and DNA damage-inducible protein 34

GCN2:

general control nonderepressible 2 kinase

HD:

Huntington’s disease

ISR:

integrated stress response

ISRIB:

integrated stress response inhibitor

PD:

Parkinson’s disease

PERK:

a PKR-like endoplasmic reticulum (ER) kinase

PKR:

protein kinase R

ROS:

reactive oxygen species

SG:

stress granules

TC:

ternary complex

uORF:

upstream open reading frame

UPR:

unfolded protein response

UTR:

untranslated region

References

  1. Ron, D. (2002) Translational control in the endoplasmic reticulum stress response, J Clin. Invest., 110, 1383-1388, https://doi.org/10.1172/jci16784.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chesnokova, E., Bal, N., and Kolosov, P. (2017) Kinases of eIF2a switch translation of mRNA subset during neuronal plasticity, Int. J. Mol. Sci., 18, 2213, https://doi.org/10.3390/ijms18102213.

    Article  CAS  PubMed Central  Google Scholar 

  3. Costa-Mattioli, M., and Walter, P. (2020) The integrated stress response: From mechanism to disease, Science, 368, eaat5314, https://doi.org/10.1126/science.aat5314.

    Article  CAS  PubMed  Google Scholar 

  4. Shacham, T., Patel, C., and Lederkremer, G. Z. (2021) PERK pathway and neurodegenerative disease: To inhibit or to activate? Biomolecules, 11, 354, https://doi.org/10.3390/biom11030354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hershey, J. W. B., and Merrick, W. C. (2000) Pathway and Mechanism of Initiation of Protein Synthesis, in Translational Control of Gene Expression (Sonenberg, N., Hershey, J. W. B., and Mathews, M. B., eds.) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, pp. 33-88.

  6. Jackson, R. J., Hellen, C. U., and Pestova, T. V. (2010) The mechanism of eukaryotic translation initiation and principles of its regulation, Nat. Rev. Mol. Cell Biol., 11, 113-127, https://doi.org/10.1038/nrm2838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Korneeva, N. L., Lamphear, B. J., Hennigan, F. L., and Rhoads, R. E. (2000) Mutually cooperative binding of eukaryotic translation initiation factor (eIF) 3 and eIF4A to human eIF4G-1, J. Biol. Chem., 275, 41369-41376, https://doi.org/10.1074/jbc.M007525200.

    Article  CAS  PubMed  Google Scholar 

  8. LeFebvre, A. K., Korneeva, N. L., Trutschl, M., Cvek, U., Duzan, R. D., et al. (2006) Translation initiation factor eIF4G-1 binds to eIF3 through the eIF3e subunit, J. Biol. Chem., 281, 22917-22932, https://doi.org/10.1074/jbc.M605418200.

    Article  CAS  PubMed  Google Scholar 

  9. Slepenkov, S. V., Korneeva, N. L., and Rhoads, R. E. (2008) Kinetic mechanism for assembly of the m7GpppG.eIF4E.eIF4G complex, J. Biol. Chem., 283, 25227-25237, https://doi.org/10.1074/jbc.M801786200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Korneeva, N. L., First, E. A., Benoit, C. A., and Rhoads, R. E. (2005) Interaction between the NH2-terminal domain of eIF4A and the central domain of eIF4G modulates RNA-stimulated ATPase activity, J. Biol. Chem., 280, 1872-1881, https://doi.org/10.1074/jbc.M406168200.

    Article  CAS  PubMed  Google Scholar 

  11. Jennings, M. D., Zhou, Y., Mohammad-Qureshi, S. S., Bennett, D., and Pavitt, G. D. (2013) eIF2B promotes eIF5 dissociation from eIF2*GDP to facilitate guanine nucleotide exchange for translation initiation, Genes Dev., 27, 2696-2707, https://doi.org/10.1101/gad.231514.113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang, X., Paulin, F. E., Campbell, L. E., Gomez, E., O’Brien, K., et al. (2001) Eukaryotic initiation factor 2B: identification of multiple phosphorylation sites in the epsilon-subunit and their functions in vivo, EMBO J., 20, 4349-4359, https://doi.org/10.1093/emboj/20.16.4349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Starck, S. R., Tsai, J. C., Chen, K., Shodiya, M., Wang, L., et al. (2016) Translation from the 5′ untranslated region shapes the integrated stress response, Science, 351, aad3867, https://doi.org/10.1126/science.aad3867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Calvo, S. E., Pagliarini, D. J., and Mootha, V. K. (2009) Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans, Proc. Natl. Acad. Sci. USA, 106, 7507-7512, https://doi.org/10.1073/pnas.0810916106.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Morris, D. R., and Geballe, A. P. (2000) Upstream open reading frames as regulators of mRNA translation, Mol. Cell Biol., 20, 8635-8642, https://doi.org/10.1128/mcb.20.23.8635-8642.2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Peccarelli, M., and Kebaara, B. W. (2014) Regulation of natural mRNAs by the nonsense-mediated mRNA decay pathway, Eukaryot. Cell, 13, 1126-1135, https://doi.org/10.1128/ec.00090-14.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Andreev, D. E., O’Connor, P. B., Fahey, C., Kenny, E. M., Terenin, I. M., et al. (2015) Translation of 5′ leaders is pervasive in genes resistant to eIF2 repression, eLife, 4, e03971, https://doi.org/10.7554/eLife.03971.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hinnebusch, A. G. (2005) Translational regulation of GCN4 and the general amino acid control of yeast, Annu. Rev. Microbiol., 59, 407-450, https://doi.org/10.1146/annurev.micro.59.031805.133833.

    Article  CAS  PubMed  Google Scholar 

  19. Harding, H. P., Novoa, I., Zhang, Y., Zeng, H., Wek, R., et al. (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells, Mol. Cell, 6, 1099-1108, https://doi.org/10.1016/S1097-2765(00)00108-8.

    Article  CAS  PubMed  Google Scholar 

  20. Vattem, K. M., and Wek, R. C. (2004) Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells, Proc. Natl. Acad. Sci. USA, 101, 11269-11274, https://doi.org/10.1073/pnas.0400541101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lu, P. D., Harding, H. P., and Ron, D. (2004) Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response, J. Cell Biol., 167, 27-33, https://doi.org/10.1083/jcb.200408003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Watatani, Y., Ichikawa, K., Nakanishi, N., Fujimoto, M., Takeda, H., et al. (2008) Stress-induced translation of ATF5 mRNA is regulated by the 5′-untranslated region, J. Biol. Chem., 283, 2543-2553, https://doi.org/10.1074/jbc.M707781200.

    Article  CAS  PubMed  Google Scholar 

  23. Dmitriev, S. E., Terenin, I. M., Andreev, D. E., Ivanov, P. A., Dunaevsky, J. E., et al. (2010) GTP-independent tRNA delivery to the ribosomal P-site by a novel eukaryotic translation factor, J. Biol. Chem., 285, 26779-26787, https://doi.org/10.1074/jbc.M110.119693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vasudevan, D., Neuman, S. D., Yang, A., Lough, L., Brown, B., et al. (2020) Translational induction of ATF4 during integrated stress response requires noncanonical initiation factors eIF2D and DENR, Nat. Commun., 11, 4677, https://doi.org/10.1038/s41467-020-18453-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bohlen, J., Harbrecht, L., Blanco, S., Clemm von Hohenberg, K., Fenzl, K., et al. (2020) DENR promotes translation reinitiation via ribosome recycling to drive expression of oncogenes including ATF4, Nat. Commun., 11, 4676, https://doi.org/10.1038/s41467-020-18452-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lu, P. D., Jousse, C., Marciniak, S. J., Zhang, Y., Novoa, I., et al. (2004) Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2, EMBO J., 23, 169-179, https://doi.org/10.1038/sj.emboj.7600030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Harding, H. P., Zhang, Y., Zeng, H., Novoa, I., Lu, P. D., et al. (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress, Mol. Cell, 11, 619-633, https://doi.org/10.1016/s1097-2765(03)00105-9.

    Article  CAS  PubMed  Google Scholar 

  28. Back, S. H., Scheuner, D., Han, J., Song, B., Ribick, M., et al. (2009) Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells, Cell Metab., 10, 13-26, https://doi.org/10.1016/j.cmet.2009.06.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pakos-Zebrucka, K., Koryga, I., Mnich, K., Ljujic, M., Samali, A., et al. (2016) The integrated stress response, EMBO Rep., 17, 1374-1395, https://doi.org/10.15252/embr.201642195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fawcett, T. W., Martindale, J. L., Guyton, K. Z., Hai, T., and Holbrook, N. J. (1999) Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response, Biochem. J., 339 (Pt 1), 135-141.

    Article  Google Scholar 

  31. Palam, L. R., Baird, T. D., and Wek, R. C. (2011) Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation, J. Biol. Chem., 286, 10939-10949, https://doi.org/10.1074/jbc.M110.216093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zinszner, H., Kuroda, M., Wang, X., Batchvarova, N., Lightfoot, R. T., et al. (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum, Genes Dev., 12, 982-995, https://doi.org/10.1101/gad.12.7.982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang, X. Z., Kuroda, M., Sok, J., Batchvarova, N., Kimmel, R., et al. (1998) Identification of novel stress-induced genes downstream of chop, EMBO J., 17, 3619-3630, https://doi.org/10.1093/emboj/17.13.3619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jauhiainen, A., Thomsen, C., Strombom, L., Grundevik, P., Andersson, C., et al. (2012) Distinct cytoplasmic and nuclear functions of the stress induced protein DDIT3/CHOP/GADD153, PLoS One, 7, e33208, https://doi.org/10.1371/journal.pone.0033208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Brostrom, M. A., Lin, X., Cade, C., Gmitter, D., and Brostrom, C. O. (1989) Loss of a calcium requirement for protein synthesis in pituitary cells following thermal or chemical stress, J. Biol. Chem., 264, 1638-1643, https://doi.org/10.1016/S0021-9258(18)94234-1.

    Article  CAS  PubMed  Google Scholar 

  36. Novoa, I., Zhang, Y., Zeng, H., Jungreis, R., Harding, H. P., et al. (2003) Stress-induced gene expression requires programmed recovery from translational repression, EMBO J., 22, 1180-1187, https://doi.org/10.1093/emboj/cdg112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Novoa, I., Zeng, H., Harding, H. P., and Ron, D. (2001) Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha, J. Cell Biol., 153, 1011-1022, https://doi.org/10.1083/jcb.153.5.1011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Marciniak, S. J., Yun, C. Y., Oyadomari, S., Novoa, I., Zhang, Y., et al. (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum, Genes Dev., 18, 3066-3077, https://doi.org/10.1101/gad.1250704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Endo, M., Mori, M., Akira, S., and Gotoh, T. (2006) C/EBP homologous protein (CHOP) is crucial for the induction of caspase-11 and the pathogenesis of lipopolysaccharide-induced inflammation, J. Immunol., 176, 6245-6253, https://doi.org/10.4049/jimmunol.176.10.6245.

    Article  CAS  PubMed  Google Scholar 

  40. Wek, R. C., Jiang, H. Y., and Anthony, T. G. (2006) Coping with stress: eIF2 kinases and translational control, Biochem. Soc. Trans., 34, 7-11, https://doi.org/10.1042/BST20060007.

    Article  CAS  PubMed  Google Scholar 

  41. Wu, C. C., Peterson, A., Zinshteyn, B., Regot, S., and Green, R. (2020) Ribosome collisions trigger general stress responses to regulate cell fate, Cell, 182, 404-416.e14, https://doi.org/10.1016/j.cell.2020.06.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lavoie, H., Li, J. J., Thevakumaran, N., Therrien, M., and Sicheri, F. (2014) Dimerization-induced allostery in protein kinase regulation, Trends Biochem. Sci., 39, 475-486, https://doi.org/10.1016/j.tibs.2014.08.004.

    Article  CAS  PubMed  Google Scholar 

  43. Jousse, C., Oyadomari, S., Novoa, I., Lu, P., Zhang, Y., et al. (2003) Inhibition of a constitutive translation initiation factor 2alpha phosphatase, CReP, promotes survival of stressed cells, J. Cell Biol., 163, 767-775, https://doi.org/10.1083/jcb.200308075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hetz, C., and Saxena, S. (2017) ER stress and the unfolded protein response in neurodegeneration, Nat. Rev. Neurol., 13, 477-491, https://doi.org/10.1038/nrneurol.2017.99.

    Article  CAS  PubMed  Google Scholar 

  45. Hamos, J. E., Oblas, B., Pulaski-Salo, D., Welch, W. J., Bole, D. G., et al. (1991) Expression of heat shock proteins in Alzheimer’s disease, Neurology, 41, 345-350, https://doi.org/10.1212/wnl.41.3.345.

    Article  CAS  PubMed  Google Scholar 

  46. Welch, W. J., and Gambetti, P. (1998) Chaperoning brain diseases, Nature, 392, 23-24, https://doi.org/10.1038/32049.

    Article  CAS  PubMed  Google Scholar 

  47. Haass, C., and Selkoe, D. J. (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide, Nat. Rev. Mol. Cell Biol., 8, 101-112, https://doi.org/10.1038/nrm2101.

    Article  CAS  PubMed  Google Scholar 

  48. Kabakov, A. E., and Gabai, V. L. (1993) Protein aggregation as primary and characteristic cell reaction to various stresses, Experientia, 49, 706-710, https://doi.org/10.1007/BF01923956.

    Article  CAS  PubMed  Google Scholar 

  49. Kouroku, Y., Fujita, E., Tanida, I., Ueno, T., Isoai, A., et al. (2007) ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation, Cell Death Differ., 14, 230-239, https://doi.org/10.1038/sj.cdd.4401984.

    Article  CAS  PubMed  Google Scholar 

  50. Rzymski, T., Milani, M., Pike, L., Buffa, F., Mellor, H. R., et al. (2010) Regulation of autophagy by ATF4 in response to severe hypoxia, Oncogene, 29, 4424-4435, https://doi.org/10.1038/onc.2010.191.

    Article  CAS  PubMed  Google Scholar 

  51. Nemoto, N., Udagawa, T., Ohira, T., Jiang, L., Hirota, K., et al. (2010) The roles of stress-activated Sty1 and Gcn2 kinases and of the protooncoprotein homologue Int6/eIF3e in responses to endogenous oxidative stress during histidine starvation, J. Mol. Biol., 404, 183-201, https://doi.org/10.1016/j.jmb.2010.09.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhan, K., Vattem, K. M., Bauer, B. N., Dever, T. E., Chen, J. J., et al. (2002) Phosphorylation of eukaryotic initiation factor 2 by heme-regulated inhibitor kinase-related protein kinases in Schizosaccharomyces pombe is important for fesistance to environmental stresses, Mol. Cell. Biol., 22, 7134-7146, https://doi.org/10.1128/mcb.22.20.7134-7146.2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Feissner, R. F., Skalska, J., Gaum, W. E., and Sheu, S. S. (2009) Crosstalk signaling between mitochondrial Ca2+ and ROS, Front. Biosci. (Landmark Ed), 14, 1197-1218, https://doi.org/10.2741/3303.

    Article  CAS  Google Scholar 

  54. Wolozin, B. (2012) Regulated protein aggregation: Stress granules and neurodegeneration, Mol. Neurodegener., 7, 56, https://doi.org/10.1186/1750-1326-7-56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Buxbaum, A. R., Haimovich, G., and Singer, R. H. (2015) In the right place at the right time: visualizing and understanding mRNA localization, Nat. Rev. Mol. Cell Biol., 16, 95-109, https://doi.org/10.1038/nrm3918.

    Article  CAS  PubMed  Google Scholar 

  56. Terenzio, M., Schiavo, G., and Fainzilber, M. (2017) Compartmentalized signaling in neurons: From cell biology to neuroscience, Neuron, 96, 667-679, https://doi.org/10.1016/j.neuron.2017.10.015.

    Article  CAS  PubMed  Google Scholar 

  57. Anderson, P., and Kedersha, N. (2008) Stress granules: The Tao of RNA triage, Trends Biochem. Sci., 33, 141-150, https://doi.org/10.1016/j.tibs.2007.12.003.

    Article  CAS  PubMed  Google Scholar 

  58. Kiebler, M. A., and Bassell, G. J. (2006) Neuronal RNA granules: movers and makers, Neuron, 51, 685-690, https://doi.org/10.1016/j.neuron.2006.08.021.

    Article  CAS  PubMed  Google Scholar 

  59. Jain, S., and Parker, R. (2013) The discovery and analysis of P Bodies, Adv. Exp. Med. Biol., 768, 23-43, https://doi.org/10.1007/978-1-4614-5107-5_3.

    Article  CAS  PubMed  Google Scholar 

  60. Buchan, J. R. (2014) mRNP granules. Assembly, function, and connections with disease, RNA Biol., 11, 1019-1030, https://doi.org/10.4161/15476286.2014.972208.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Liu-Yesucevitz, L., Bilgutay, A., Zhang, Y. J., Vanderweyde, T., Citro, A., et al. (2010) Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue, PLoS One, 5, e13250, https://doi.org/10.1371/journal.pone.0013250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Thomas, M. G., Loschi, M., Desbats, M. A., and Boccaccio, G. L. (2011) RNA granules: the good, the bad and the ugly, Cell. Signall., 23, 324-334, https://doi.org/10.1016/j.cellsig.2010.08.011.

    Article  CAS  Google Scholar 

  63. Vanderweyde, T., Yu, H., Varnum, M., Liu-Yesucevitz, L., Citro, A., et al. (2012) Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies, J. Neurosci., 32, 8270-8283, https://doi.org/10.1523/jneurosci.1592-12.2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Vanderweyde, T., Apicco, D. J., Youmans-Kidder, K., Ash, P. E., Cook, C., et al. (2016) Interaction of tau with the RNA-binding protein TIA1 regulates tau pathophysiology and toxicity, Cell Rep., 15, 1455-1466, https://doi.org/10.1016/j.celrep.2016.04.045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bentmann, E., Haass, C., and Dormann, D. (2013) Stress granules in neurodegeneration – lessons learnt from TAR DNA binding protein of 43 kDa and fused in sarcoma, FEBS J., 280, 4348-4370, https://doi.org/10.1111/febs.12287.

    Article  CAS  PubMed  Google Scholar 

  66. Abrakhi, S., Kretov, D. A., Desforges, B., Dobra, I., Bouhss, A., et al. (2017) Nanoscale analysis reveals the maturation of neurodegeneration-associated protein aggregates: Grown in mRNA granules then released by stress granule proteins, ACS Nano, 11, 7189-7200, https://doi.org/10.1021/acsnano.7b03071.

    Article  CAS  PubMed  Google Scholar 

  67. Han, J., Back, S. H., Hur, J., Lin, Y. H., Gildersleeve, R., et al. (2013) ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death, Nat. Cell Biol., 15, 481-490, https://doi.org/10.1038/ncb2738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Galehdar, Z., Swan, P., Fuerth, B., Callaghan, S. M., Park, D. S., et al. (2010) Neuronal apoptosis induced by endoplasmic reticulum stress is regulated by ATF4-CHOP-mediated induction of the Bcl-2 homology 3-only member PUMA, J. Neurosci., 30, 16938-16948, https://doi.org/10.1523/jneurosci.1598-10.2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ren, D., Tu, H. C., Kim, H., Wang, G. X., Bean, G. R., et al. (2010) BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program, Science, 330, 1390-1393, https://doi.org/10.1126/science.1190217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Paschen, W., Gissel, C., Linden, T., Althausen, S., and Doutheil, J. (1998) Activation of gadd153 expression through transient cerebral ischemia: evidence that ischemia causes endoplasmic reticulum dysfunction, Brain Res. Mol. Brain Res., 60, 115-122, https://doi.org/10.1016/s0169-328x(98)00180-6.

    Article  CAS  PubMed  Google Scholar 

  71. Jin, K., Mao, X. O., Eshoo, M. W., Nagayama, T., Minami, M., et al. (2001) Microarray analysis of hippocampal gene expression in global cerebral ischemia, Ann. Neurol., 50, 93-103, https://doi.org/10.1002/ana.1073.

    Article  CAS  PubMed  Google Scholar 

  72. Morimoto, N., Oida, Y., Shimazawa, M., Miura, M., Kudo, T., et al. (2007) Involvement of endoplasmic reticulum stress after middle cerebral artery occlusion in mice, Neuroscience, 147, 957-967, https://doi.org/10.1016/j.neuroscience.2007.04.017.

    Article  CAS  PubMed  Google Scholar 

  73. Niizuma, K., Endo, H., Nito, C., Myer, D. J., and Chan, P. H. (2009) Potential role of PUMA in delayed death of hippocampal CA1 neurons after transient global cerebral ischemia, Stroke, 40, 618-625, https://doi.org/10.1161/strokeaha.108.524447.

    Article  CAS  PubMed  Google Scholar 

  74. Holtz, W. A., and O’Malley, K. L. (2003) Parkinsonian mimetics induce aspects of unfolded protein response in death of dopaminergic neurons, J. Biol. Chem., 278, 19367-19377, https://doi.org/10.1074/jbc.M211821200.

    Article  CAS  PubMed  Google Scholar 

  75. Silva, R. M., Ries, V., Oo, T. F., Yarygina, O., Jackson-Lewis, V., et al. (2005) CHOP/GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism, J. Neurochem., 95, 974-986, https://doi.org/10.1111/j.1471-4159.2005.03428.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kieran, D., Woods, I., Villunger, A., Strasser, A., and Prehn, J. H. (2007) Deletion of the BH3-only protein puma protects motoneurons from ER stress-induced apoptosis and delays motoneuron loss in ALS mice, Proc. Natl. Acad. Sci. USA, 104, 20606-20611, https://doi.org/10.1073/pnas.0707906105.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Hiramatsu, N., Messah, C., Han, J., LaVail, M. M., Kaufman, R. J., et al. (2014) Translational and posttranslational regulation of XIAP by eIF2alpha and ATF4 promotes ER stress-induced cell death during the unfolded protein response, Mol. Biol. Cell, 25, 1411-1420, https://doi.org/10.1091/mbc.E13-11-0664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chang, R. C., Wong, A. K., Ng, H. K., and Hugon, J. (2002) Phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha) is associated with neuronal degeneration in Alzheimer’s disease, Neuroreport, 13, 2429-2432.

    Article  CAS  Google Scholar 

  79. Hoozemans, J. J., van Haastert, E. S., Eikelenboom, P., de Vos, R. A., Rozemuller, J. M., et al. (2007) Activation of the unfolded protein response in Parkinson’s disease, Biochem. Biophys. Res. Commun., 354, 707-711, https://doi.org/10.1016/j.bbrc.2007.01.043.

    Article  CAS  PubMed  Google Scholar 

  80. Atkin, J. D., Farg, M. A., Walker, A. K., McLean, C., Tomas, D., et al. (2008) Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis, Neurobiol. Dis., 30, 400-407, https://doi.org/10.1016/j.nbd.2008.02.009.

    Article  CAS  PubMed  Google Scholar 

  81. Chou, A., Krukowski, K., Jopson, T., Zhu, P. J., Costa-Mattioli, M., et al. (2017) Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury, Proc. Natl. Acad. Sci. USA, 114, E6420-E6426, https://doi.org/10.1073/pnas.1707661114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Nijholt, D. A., van Haastert, E. S., Rozemuller, A. J., Scheper, W., and Hoozemans, J. J. (2012) The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies, J. Pathol., 226, 693-702, https://doi.org/10.1002/path.3969.

    Article  CAS  PubMed  Google Scholar 

  83. Fernández-Vizarra, P., Fernández, A. P., Castro-Blanco, S., Serrano, J., Bentura, M. L., et al. (2004) Intra- and extracellular Abeta and PHF in clinically evaluated cases of Alzheimer’s disease, Histol. Histopathol., 19, 823-844, https://doi.org/10.14670/hh-19.823.

    Article  PubMed  Google Scholar 

  84. O'Connor, T., Sadleir, K. R., Maus, E., Velliquette, R. A., Zhao, J., et al. (2008) Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis, Neuron, 60, 988-1009, https://doi.org/10.1016/j.neuron.2008.10.047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Mouton-Liger, F., Paquet, C., Dumurgier, J., Bouras, C., Pradier, L., et al. (2012) Oxidative stress increases BACE1 protein levels through activation of the PKR-eIF2alpha pathway, Biochim. Biophys. Acta, 1822, 885-896, https://doi.org/10.1016/j.bbadis.2012.01.009.

    Article  CAS  PubMed  Google Scholar 

  86. Ma, T., Trinh, M. A., Wexler, A. J., Bourbon, C., Gatti, E., et al. (2013) Suppression of eIF2alpha kinases alleviates Alzheimer’s disease-related plasticity and memory deficits, Nat. Neurosci., 16, 1299-1305, https://doi.org/10.1038/nn.3486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Baleriola, J., Walker, C. A., Jean, Y. Y., Crary, J. F., Troy, C. M., et al. (2014) Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions, Cell, 158, 1159-1172, https://doi.org/10.1016/j.cell.2014.07.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lange, P. S., Chavez, J. C., Pinto, J. T., Coppola, G., Sun, C. W., et al. (2008) ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo, J. Exp. Med., 205, 1227-1242, https://doi.org/10.1084/jem.20071460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yang, W., Zhou, X., Zimmermann, H. R., Cavener, D. R., Klann, E., et al. (2016) Repression of the eIF2α kinase PERK alleviates mGluR-LTD impairments in a mouse model of Alzheimer’s disease, Neurobiol. Aging, 41, 19-24, https://doi.org/10.1016/j.neurobiolaging.2016.02.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Gully, J. C., Sergeyev, V. G., Bhootada, Y., Mendez-Gomez, H., Meyers, C. A., et al. (2016) Up-regulation of activating transcription factor 4 induces severe loss of dopamine nigral neurons in a rat model of Parkinson’s disease, Neurosci. Lett., 627, 36-41, https://doi.org/10.1016/j.neulet.2016.05.039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Bellucci, A., Navarria, L., Zaltieri, M., Falarti, E., Bodei, S., et al. (2011) Induction of the unfolded protein response by α-synuclein in experimental models of Parkinson’s disease, J. Neurochem., 116, 588-605, https://doi.org/10.1111/j.1471-4159.2010.07143.x.

    Article  CAS  PubMed  Google Scholar 

  92. Cooper, A. A., Gitler, A. D., Cashikar, A., Haynes, C. M., Hill, K. J., et al. (2006) Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models, Science, 313, 324-328, https://doi.org/10.1126/science.1129462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ilieva, E. V., Ayala, V., Jové, M., Dalfó, E., Cacabelos, D., et al. (2007) Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis, Brain, 130, 3111-3123, https://doi.org/10.1093/brain/awm190.

    Article  PubMed  Google Scholar 

  94. Kikuchi, H., Almer, G., Yamashita, S., Guégan, C., Nagai, M., et al. (2006) Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model, Proc. Natl. Acad. Sci. USA, 103, 6025-6030, https://doi.org/10.1073/pnas.0509227103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Urushitani, M., Ezzi, S. A., Matsuo, A., Tooyama, I., and Julien, J. P. (2008) The endoplasmic reticulum-Golgi pathway is a target for translocation and aggregation of mutant superoxide dismutase linked to ALS, FASEB J., 22, 2476-2487, https://doi.org/10.1096/fj.07-092783.

    Article  CAS  PubMed  Google Scholar 

  96. Farg, M. A., Soo, K. Y., Warraich, S. T., Sundaramoorthy, V., Blair, I. P., et al. (2013) Ataxin-2 interacts with FUS and intermediate-length polyglutamine expansions enhance FUS-related pathology in amyotrophic lateral sclerosis, Human Mol. Genet., 22, 717-728, https://doi.org/10.1093/hmg/dds479.

    Article  CAS  Google Scholar 

  97. Hetz, C., Russelakis-Carneiro, M., Maundrell, K., Castilla, J., and Soto, C. (2003) Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein, EMBO J., 22, 5435-5445, https://doi.org/10.1093/emboj/cdg537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Carnemolla, A., Fossale, E., Agostoni, E., Michelazzi, S., Calligaris, R., et al. (2009) Rrs1 is involved in endoplasmic reticulum stress response in Huntington’s disease, J. Biol. Chem., 284, 18167-18173, https://doi.org/10.1074/jbc.M109.018325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Vitet, H., Brandt, V., and Saudou, F. (2020) Traffic signaling: New functions of huntingtin and axonal transport in neurological disease, Curr. Opin. Neurobiol., 63, 122-130, https://doi.org/10.1016/j.conb.2020.04.001.

    Article  CAS  PubMed  Google Scholar 

  100. Kandel, E. R. (2001) The molecular biology of memory storage: a dialogue between genes and synapses, Science, 294, 1030-1038, https://doi.org/10.1126/science.1067020.

    Article  CAS  PubMed  Google Scholar 

  101. Klann, E., and Sweatt, J. D. (2008) Altered protein synthesis is a trigger for long-term memory formation, Neurobiol. Learn Mem., 89, 247-259, https://doi.org/10.1016/j.nlm.2007.08.009.

    Article  CAS  PubMed  Google Scholar 

  102. Trinh, M. A., and Klann, E. (2013) Translational control by eIF2α kinases in long-lasting synaptic plasticity and long-term memory, Neurobiol. Learn Mem., 105, 93-99, https://doi.org/10.1016/j.nlm.2013.04.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Di Prisco, G. V., Huang, W., Buffington, S. A., Hsu, C. C., Bonnen, P. E., et al. (2014) Translational control of mGluR-dependent long-term depression and object-place learning by eIF2alpha, Nat. Neurosci., 17, 1073-1082, https://doi.org/10.1038/nn.3754.

    Article  CAS  PubMed  Google Scholar 

  104. Costa-Mattioli, M., Gobert, D., Stern, E., Gamache, K., Colina, R., et al. (2007) eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory, Cell, 129, 195-206, https://doi.org/10.1016/j.cell.2007.01.050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Jiang, Z., Belforte, J. E., Lu, Y., Yabe, Y., Pickel, J., et al. (2010) eIF2{alpha} phosphorylation-dependent translation in CA1 pyramidal cells impairs hippocampal memory consolidation without affecting general translation, J. Neurosci., 30, 2582-2594, https://doi.org/10.1523/jneurosci.3971-09.2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Trinh, M. A., Ma, T., Kaphzan, H., Bhattacharya, A., Antion, M. D., et al. (2014) The eIF2α kinase PERK limits the expression of hippocampal metabotropic glutamate receptor-dependent long-term depression, Learn. Memory, 21, 298-304, https://doi.org/10.1101/lm.032219.113.

    Article  CAS  Google Scholar 

  107. Silva, A. J., Kogan, J. H., Frankland, P. W., and Kida, S. (1998) CREB and memory, Annu. Rev. Neurosci., 21, 127-148, https://doi.org/10.1146/annurev.neuro.21.1.127.

    Article  CAS  PubMed  Google Scholar 

  108. Yin, J. C., Wallach, J. S., Del Vecchio, M., Wilder, E. L., Zhou, H., et al. (1994) Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila, Cell, 79, 49-58, https://doi.org/10.1016/0092-8674(94)90399-9.

    Article  CAS  PubMed  Google Scholar 

  109. Bartsch, D., Ghirardi, M., Skehel, P. A., Karl, K. A., Herder, S. P., et al. (1995) Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change, Cell, 83, 979-992, https://doi.org/10.1016/0092-8674(95)90213-9.

    Article  CAS  PubMed  Google Scholar 

  110. Chen, A., Muzzio, I. A., Malleret, G., Bartsch, D., Verbitsky, M., et al. (2003) Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins, Neuron, 39, 655-669, https://doi.org/10.1016/s0896-6273(03)00501-4.

    Article  CAS  PubMed  Google Scholar 

  111. Huang, W., Placzek, A. N., Di Prisco, G. V., Khatiwada, S., Sidrauski, C., et al. (2016) Translational control by eIF2α phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine, eLife, 5, e12052, https://doi.org/10.7554/eLife.12052.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Nadif Kasri, N., Nakano-Kobayashi, A., and Van Aelst, L. (2011) Rapid synthesis of the X-linked mental retardation protein OPHN1 mediates mGluR-dependent LTD through interaction with the endocytic machinery, Neuron, 72, 300-315, https://doi.org/10.1016/j.neuron.2011.09.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Costa-Mattioli, M., Gobert, D., Harding, H., Herdy, B., Azzi, M., et al. (2005) Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2, Nature, 436, 1166-1173, https://doi.org/10.1038/nature03897.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zhu, P. J., Huang, W., Kalikulov, D., Yoo, J. W., Placzek, A. N., et al. (2011) Suppression of PKR promotes network excitability and enhanced cognition by interferon-γ-mediated disinhibition, Cell, 147, 1384-1396, https://doi.org/10.1016/j.cell.2011.11.029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Trinh, M. A., Kaphzan, H., Wek, R. C., Pierre, P., Cavener, D. R., et al. (2012) Brain-specific disruption of the eIF2alpha kinase PERK decreases ATF4 expression and impairs behavioral flexibility, Cell Rep., 1, 676-688, https://doi.org/10.1016/j.celrep.2012.04.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Liu, J., Pasini, S., Shelanski, M. L., and Greene, L. A. (2014) Activating transcription factor 4 (ATF4) modulates post-synaptic development and dendritic spine morphology, Front. Cell. Neurosci., 8, 177, https://doi.org/10.3389/fncel.2014.00177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Moreno, J. A., Radford, H., Peretti, D., Steinert, J. R., Verity, N., et al. (2012) Sustained translational repression by eIF2alpha-P mediates prion neurodegeneration, Nature, 485, 507-511, https://doi.org/10.1038/nature11058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Green, T. A., Alibhai, I. N., Unterberg, S., Neve, R. L., Ghose, S., et al. (2008) Induction of activating transcription factors (ATFs) ATF2, ATF3, and ATF4 in the nucleus accumbens and their regulation of emotional behavior, J. Neurosci., 28, 2025-2032, https://doi.org/10.1523/jneurosci.5273-07.2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Fan, R., Schrott, L. M., Snelling, S., Ndi, J., Arnold, T.,et al. (2015) Chronic oxycodone induces integrated stress response in rat brain, BMC Neurosci., 16, 58, https://doi.org/10.1186/s12868-015-0197-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Fan, R., Schrott, L. M., Arnold, T., Snelling, S., Rao, M., et al. (2018) Chronic oxycodone induces axonal degeneration in rat brain, BMC Neurosci., 19, 15, https://doi.org/10.1186/s12868-018-0417-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Fan, R., Schrott, L. M., Snelling, S., Felty, J., Graham, D., et al. (2020) Carbonyl-protein content increases in brain and blood of female rats after chronic oxycodone treatment, BMC Neurosci., 21, 4, https://doi.org/10.1186/s12868-020-0552-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ballesteros-Yanez, I., Ambrosio, E., Benavides-Piccione, R., Perez, J., et al. (2007) The effects of morphine self-administration on cortical pyramidal cell structure in addiction-prone lewis rats, Cerebral Cortex, 17, 238-249, https://doi.org/10.1093/cercor/bhj142.

    Article  CAS  PubMed  Google Scholar 

  123. Placzek, A. N., Di Prisco, G. V., Khatiwada, S., Sgritta, M., Huang, W., et al. (2016) eIF2α-mediated translational control regulates the persistence of cocaine-induced LTP in midbrain dopamine neurons, eLife, 5, e17517, https://doi.org/10.7554/eLife.17517.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Placzek, A. N., Molfese, D. L., Khatiwada, S., Di Prisco, G. V., Huang, W., et al. (2016) Translational control of nicotine-evoked synaptic potentiation in mice and neuronal responses in human smokers by eIF2α, eLife, 5, e12056, https://doi.org/10.7554/eLife.12056.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Melas, P. A., Qvist, J. S., Deidda, M., Upreti, C., Wei, Y. B., et al. (2018) Cannabinoid modulation of eukaryotic initiation factors (eIF2α and eIF2B1) and behavioral cross-sensitization to cocaine in adolescent rats, Cell Rep., 22, 2909-2923, https://doi.org/10.1016/j.celrep.2018.02.065.

    Article  CAS  PubMed  Google Scholar 

  126. Price, T. J., and Géranton, S. M. (2009) Translating nociceptor sensitivity: the role of axonal protein synthesis in nociceptor physiology, Eur. J. Neurosci., 29, 2253-2263, https://doi.org/10.1111/j.1460-9568.2009.06786.x.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Melemedjian, O. K., and Khoutorsky, A. (2015) Translational control of chronic pain, Prog. Mol. Biol. Transl. Sci., 131, 185-213, https://doi.org/10.1016/bs.pmbts.2014.11.006.

    Article  PubMed  Google Scholar 

  128. Khoutorsky, A., and Price, T. J. (2018) Translational control mechanisms in persistent pain, Trends Neurosci., 41, 100-114, https://doi.org/10.1016/j.tins.2017.11.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Yousuf, M. S., Shiers, S. I., Sahn, J. J., and Price, T. J. (2021) Pharmacological manipulation of translation as a therapeutic target for chronic pain, Pharmacol. Rev., 73, 59-88, https://doi.org/10.1124/pharmrev.120.000030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Géranton, S. M., Jiménez-Díaz, L., Torsney, C., Tochiki, K. K., Stuart, S. A., et al. (2009) A rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states, J. Neurosci., 29, 15017-15027, https://doi.org/10.1523/jneurosci.3451-09.2009.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Asante, C. O., Wallace, V. C., and Dickenson, A. H. (2010) Mammalian target of rapamycin signaling in the spinal cord is required for neuronal plasticity and behavioral hypersensitivity associated with neuropathy in the rat, J. Pain Official J. Am. Pain Soc., 11, 1356-1367, https://doi.org/10.1016/j.jpain.2010.03.013.

    Article  CAS  Google Scholar 

  132. Obara, I., Tochiki, K. K., Géranton, S. M., Carr, F. B., Lumb, B. M., et al. (2011) Systemic inhibition of the mammalian target of rapamycin (mTOR) pathway reduces neuropathic pain in mice, Pain, 152, 2582-2595, https://doi.org/10.1016/j.pain.2011.07.025.

    Article  CAS  PubMed  Google Scholar 

  133. Khoutorsky, A., Sorge, R. E., Prager-Khoutorsky, M., Pawlowski, S. A., Longo, G., et al. (2016) eIF2alpha phosphorylation controls thermal nociception, Proc. Natl. Acad. Sci. USA, 113, 11949-11954, https://doi.org/10.1073/pnas.1614047113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Braz, J. M., and Basbaum, A. I. (2010) Differential ATF3 expression in dorsal root ganglion neurons reveals the profile of primary afferents engaged by diverse noxious chemical stimuli, Pain, 150, 290-301, https://doi.org/10.1016/j.pain.2010.05.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Dong, L., Guarino, B. B., Jordan-Sciutto, K. L., and Winkelstein, B. A. (2011) Activating transcription factor 4, a mediator of the integrated stress response, is increased in the dorsal root ganglia following painful facet joint distraction, Neuroscience, 193, 377-386, https://doi.org/10.1016/j.neuroscience.2011.07.059.

    Article  CAS  PubMed  Google Scholar 

  136. Leegwater, P. A., Vermeulen, G., Könst, A. A., Naidu, S., Mulders, J., et al. (2001) Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter, Nat. Genet., 29, 383-388, https://doi.org/10.1038/ng764.

    Article  CAS  PubMed  Google Scholar 

  137. Van der Knaap, M. S., Leegwater, P. A., Konst, A. A., Visser, A., Naidu, S., et al. (2002) Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter, Ann. Neurol., 51, 264-270, https://doi.org/10.1002/ana.10112.

    Article  CAS  PubMed  Google Scholar 

  138. Bugiani, M., Boor, I., Powers, J. M., Scheper, G. C., and van der Knaap, M. S. (2010) Leukoencephalopathy with vanishing white matter: a review, J. Neuropathol. Exp. Neurol., 69, 987-996, https://doi.org/10.1097/NEN.0b013e3181f2eafa.

    Article  PubMed  Google Scholar 

  139. Liu, R., van der Lei, H. D., Wang, X., Wortham, N. C., Tang, H., et al. (2011) Severity of vanishing white matter disease does not correlate with deficits in eIF2B activity or the integrity of eIF2B complexes, Hum. Mutat., 32, 1036-1045, https://doi.org/10.1002/humu.21535.

    Article  CAS  PubMed  Google Scholar 

  140. Wong, Y. L., LeBon, L., Basso, A. M., Kohlhaas, K. L., Nikkel, A. L., et al. (2019) eIF2B activator prevents neurological defects caused by a chronic integrated stress response, eLife, 8, e42940, https://doi.org/10.7554/eLife.42940.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Wong, Y. L., LeBon, L., Edalji, R., Lim, H. B., Sun, C., et al. (2018) The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes, eLife, 7, e32733, https://doi.org/10.7554/eLife.32733.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Borck, G., Shin, B. S., Stiller, B., Mimouni-Bloch, A., Thiele, H., et al. (2012) eIF2gamma mutation that disrupts eIF2 complex integrity links intellectual disability to impaired translation initiation, Mol. Cell, 48, 641-646, https://doi.org/10.1016/j.molcel.2012.09.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Julier, C., and Nicolino, M. (2010) Wolcott–Rallison syndrome, Orphanet J. Rare Dis., 5, 29, https://doi.org/10.1186/1750-1172-5-29.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Eyries, M., Montani, D., Girerd, B., Perret, C., Leroy, A., et al. (2014) EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension, Nat. Genet., 46, 65-69, https://doi.org/10.1038/ng.2844.

    Article  CAS  PubMed  Google Scholar 

  145. Longchamp, A., Mirabella, T., Arduini, A., MacArthur, M. R., Das, A., et al. (2018) Amino acid restriction triggers angiogenesis via GCN2/ATF4 regulation of VEGF and H(2)S production, Cell, 173, 117-129.e114, https://doi.org/10.1016/j.cell.2018.03.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Rubovitch, V., Barak, S., Rachmany, L., Goldstein, R. B., Zilberstein, Y., et al. (2015) The neuroprotective effect of salubrinal in a mouse model of traumatic brain injury, Neuromol. Med., 17, 58-70, https://doi.org/10.1007/s12017-015-8340-3.

    Article  CAS  Google Scholar 

  147. Halliday, M., Radford, H., Zents, K. A. M., Molloy, C., Moreno, J. A., et al. (2017) Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice, Brain, 140, 1768-1783, https://doi.org/10.1093/brain/awx074.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Moreno, J. A., Halliday, M., Molloy, C., Radford, H., Verity, N., et al. (2013) Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice, Sci. Transl. Med., 5, 206ra138, https://doi.org/10.1126/scitranslmed.3006767.

    Article  CAS  PubMed  Google Scholar 

  149. Radford, H., Moreno, J. A., Verity, N., Halliday, M., and Mallucci, G. R. (2015) PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia, Acta Neuropathol., 130, 633-642, https://doi.org/10.1007/s00401-015-1487-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Rojas-Rivera, D., Delvaeye, T., Roelandt, R., Nerinckx, W., Augustyns, K., et al. (2017) When PERK inhibitors turn out to be new potent RIPK1 inhibitors: critical issues on the specificity and use of GSK2606414 and GSK2656157, Cell Death Differ., 24, 1100-1110, https://doi.org/10.1038/cdd.2017.58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Halliday, M., Radford, H., Sekine, Y., Moreno, J., Verity, N., et al. (2015) Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity, Cell Death Dis., 6, e1672, https://doi.org/10.1038/cddis.2015.49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Bruch, J., Xu, H., Rösler, T. W., De Andrade, A., Kuhn, P. H., et al. (2017) PERK activation mitigates tau pathology in vitro and in vivo, EMBO Mol. Med., 9, 371-384, https://doi.org/10.15252/emmm.201606664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Sidrauski, C., Acosta-Alvear, D., Khoutorsky, A., Vedantham, P., Hearn, B. R., et al. (2013) Pharmacological brake-release of mRNA translation enhances cognitive memory, eLife Sci., 2, e00498, https://doi.org/10.7554/eLife.00498.

    Article  CAS  Google Scholar 

  154. Sidrauski, C., Tsai, J. C., Kampmann, M., Hearn, B. R., Vedantham, P., et al. (2015) Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response, eLife, 4, e07314, https://doi.org/10.7554/eLife.07314.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Sekine, Y., Zyryanova, A., Crespillo-Casado, A., Fischer, P. M., Harding, H. P., et al. (2015) Stress responses. Mutations in a translation initiation factor identify the target of a memory-enhancing compound, Science, 348, 1027-1030, https://doi.org/10.1126/science.aaa6986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Tsai, J. C., Miller-Vedam, L. E., Anand, A. A., Jaishankar, P., Nguyen, H. C., et al. (2018) Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule, Science, 359, eaaq0939, https://doi.org/10.1126/science.aaq0939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Zyryanova, A. F., Weis, F., Faille, A., Alard, A. A., Crespillo-Casado, A., et al. (2018) Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B, Science, 359, 1533-1536, https://doi.org/10.1126/science.aar5129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Rabouw, H. H., Langereis, M. A., Anand, A. A., Visser, L. J., de Groot, R. J., et al. (2019) Small molecule ISRIB suppresses the integrated stress response within a defined window of activation, Proc. Natl. Acad. Sci. USA, 116, 2097-2102, https://doi.org/10.1073/pnas.1815767116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Hu, J., Rho, H. S., Newman, R. H., Hwang, W., Neiswinger, J., et al. (2014) Global analysis of phosphorylation networks in humans, Biochim. Biophys. Acta, 1844, 224-231, https://doi.org/10.1016/j.bbapap.2013.03.009.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The author is grateful to the Department of Pharmacology, Toxicology and Neuroscience, the Department of Emergency Medicine, and Feist-Weiller Cancer Center for their support. The author expresses her gratitude to Dr. Dmitry N. Lyabin and Evgeniya V. Serebrova for help in manuscript preparation.

Funding

This study was financially supported by NIH (Grants Nos. 2R01GM20818, R01GM20818, and R01GM20818-32).

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  1. Louisiana State University Health Science Center, 71103, Shreveport, LA, USA

    Nadejda L. Korneeva

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Correspondence to Nadejda L. Korneeva.

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The author declares no conflicts of interest. This article does not contain any studies with human participants or animals performed by the author.

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Translated from Uspekhi Biologicheskoi Khimii, 2022, Vol. 62, pp. 243-278.

In memory of a great scientist and my Teacher

and Mentor Lev Pavlovich Ovchinnikov

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Korneeva, N.L. Integrated Stress Response in Neuronal Pathology and in Health. Biochemistry Moscow 87 (Suppl 1), S111–S127 (2022). https://doi.org/10.1134/S0006297922140103

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