Journal of Molecular Neuroscience

, Volume 57, Issue 4, pp 529–537 | Cite as

Unfolded Protein Response Pathways in Neurodegenerative Diseases

  • Syed Zahid Ali Shah
  • Deming Zhao
  • Sher Hayat Khan
  • Lifeng YangEmail author


The aggregation of disease-specific misfolded proteins resulting in endoplasmic reticulum stress is associated with early pathological events in many neurodegenerative diseases, and apoptotic signaling is initiated when the stress goes beyond the maximum threshold level of endoplasmic reticulum stress sensors. All eukaryotic cells respond to the accumulation of unfolded proteins in the endoplasmic reticulum (ER) by signaling an adaptive pathway termed as unfolded protein response (UPR). Recently, the focus of research shifted from work on specific proteins as pathogenesis in these neurodegenerative diseases towards a more specific generic pathway known as UPR. ER is a major organelle for protein quality control, and cellular stress disrupts normal functioning of ER. The UPR acts as a protective mechanism during endoplasmic reticulum stress, but persistent long-term stress triggers UPR-mediated apoptotic pathways ultimately leading to cell death. Here in this review, we will briefly summarize the molecular events of endoplasmic reticulum stress-associated UPR signaling pathways and their potential therapeutic role in neurodegenerative diseases.


Endoplasmic reticulum (ER) Unfolded protein response (UPR) Neurodegenerative diseases and apoptotic signaling 



This work is supported by 948 projects (2014-S9) and the Program for Cheung Kong Scholars and Innovative Research Team in University of China (No. IRT0866).


  1. Abisambra JF et al (2013) Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. J Neurosci 33(22):9498–9507PubMedCentralCrossRefPubMedGoogle Scholar
  2. Argon Y, Simen BB (1999) GRP94, an ER chaperone with protein and peptide binding properties. Seminars in cell & developmental biology 10(5):495–505CrossRefGoogle Scholar
  3. Bellucci A, Navarria L, Zaltieri M, Falarti E, Bodei S, Sigala S, Battistin L, Spillantini M, Missale C, Spano P (2011) Induction of the unfolded proteinresponse by alpha-synuclein in experimental models of Parkinson’s disease. J Neurochem 116:588e605Google Scholar
  4. Benbrook DM, Long A (2012) Integration of autophagy, proteasomal degradation, unfolded protein response and apoptosis. Exp Oncol 34:286–297PubMedGoogle Scholar
  5. Bernales S, McDonald KL, Walter P (2006) Autophagy counter balances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol 4:e423PubMedCentralCrossRefPubMedGoogle Scholar
  6. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nature cell biology 2(6):326–332CrossRefPubMedGoogle Scholar
  7. Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D et al (2005) A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 307:935e939CrossRefGoogle Scholar
  8. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415(6867):92–96CrossRefPubMedGoogle Scholar
  9. Chakrabarti A, Chen AW, Varner JD (2011) A review of the mammalian unfolded protein response. Biotechnol Bioeng 108:2777–2793PubMedCentralCrossRefPubMedGoogle Scholar
  10. Chen X, Yin XM (2011) Coordination of autophagy and the proteasome in resolving endoplasmic reticulum stress. Vet Pathol 48:245–253CrossRefPubMedGoogle Scholar
  11. Chevalier-Larsen E, Holzbaur ELF (2006) Axonal transport and neurodegenerative disease. Biochim Biophys Acta 1762:1094–1108CrossRefPubMedGoogle Scholar
  12. Chung KT, Shen Y, Hendershot LM (2000) BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP. The Journal of biological chemistry 277(49):47557–47563CrossRefGoogle Scholar
  13. Chung CY et al (2013) Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. Science 342(6161):983–987PubMedCentralCrossRefPubMedGoogle Scholar
  14. Cornejo VH, Hetz C (2013) The unfolded protein response in Alzheimer’s disease. (Review). Semin Immunopathol 35:277–292CrossRefPubMedGoogle Scholar
  15. Credle JJ, Forcelli PA, Delannoy M, Oaks AW, Permaul E, Berry DL, Duka V, Wills J, Sidhu A (2015) α-Synuclein-mediated inhibition of ATF6 processing into COPII vesicles disrupts UPR signaling in Parkinson’s disease. Neurobiology of Disease 76:112–125CrossRefPubMedGoogle Scholar
  16. Cullinan SB, Diehl JA (2006) Coordination of ER and oxidativestress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol 38:317–332CrossRefPubMedGoogle Scholar
  17. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (2003) Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23:7198–7209PubMedCentralCrossRefPubMedGoogle Scholar
  18. Ding WX, Ni HM, Gao W, Yoshimori T, Stolz DB, Ron D (2007) Linking of autophagy to ubiquitin–proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol 171:513–524PubMedCentralCrossRefPubMedGoogle Scholar
  19. Doyle KM, Adrienne MG, Sanjeev G, Sandra JMH, Afshin S (2011) Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders. J Cell Mol Med 15(10):2025–2039Google Scholar
  20. Ellgaard L, Helenius A (2003) Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol 4:181–191CrossRefPubMedGoogle Scholar
  21. Ellgaard L, Molinari M, Helenius A (1999) Setting the standards: quality control in the secretory pathway. Science 286:1882–1888CrossRefPubMedGoogle Scholar
  22. Fernandez-Fernandez MR, Ferrer I, Lucas JJ (2011) Impaired ATF6α processing, decreased Rheb and neuronal cell cycle re-entry in Huntington’s disease. Neurobiol Dis 41:23–32CrossRefPubMedGoogle Scholar
  23. Fewell SW, Travers KJ, Weissman JS, Brodsky JL (2001) The action of molecular chaperones in the early secretory pathway. Annu Rev Genet 35:149–191CrossRefPubMedGoogle Scholar
  24. Fra AM, Fagioli C, Finazzi D, Sitia R, Alberini CM (1993) Quality control of ER synthesized proteins:an exposed thiol group as a three-ways witch mediating assembly, retention and degradation. EMBO J 12:4755–4761PubMedCentralPubMedGoogle Scholar
  25. Freiden PJ, Gaut JR, Hendershot LM (1992) Interconversion of three differentially modified and assembled forms of BiP. The EMBO journal 11(1):63–70PubMedCentralPubMedGoogle Scholar
  26. Gething MJ (1999) Role and regulation of the ER chaperone BiP. Seminars in cell & developmental biology 10(5):465–472CrossRefGoogle Scholar
  27. Glembotski CC (2007) Endoplasmic reticulum stress in the heart. Circ Res 101:975–984CrossRefPubMedGoogle Scholar
  28. Han J, Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, Yuan CL, Krokowski D, Wang S, Hatzoglou M et al (2013) ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol 159:481–490CrossRefGoogle Scholar
  29. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Molecular cell 6(5):1099–1108CrossRefPubMedGoogle Scholar
  30. Haze K, Yoshida H, Yanagi H, Yura T, Mori K (1999) Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Molecular biology of the cell 10(11):3787–3799PubMedCentralCrossRefPubMedGoogle Scholar
  31. Hebert DN, Molinari M (2007) In and out of the ER:protein folding, quality control, degradation, and related human diseases. Physiol Rev 87:1377–1408CrossRefPubMedGoogle Scholar
  32. Hetz C, Glimcher LH (2009) Fine-tuning of the unfolded protein response: Assembling the IRE1alpha interactome. Molecular cell 35(5):551–561PubMedCentralCrossRefPubMedGoogle Scholar
  33. Hetz C, Russelakis-Carneiro M, Walchli S, Carboni S, Vial-Knecht E, Maundrell K, Castella J, Soto C (2005) The disulfide isomerase Grp58 is a protective factor against prion neurotoxicity. J Neurosci 25:2793–2802CrossRefPubMedGoogle Scholar
  34. Hetz C, Russelakis-Carneiro M, Maundrell K, Castilla J, Soto C (2003) Caspase 12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. EMBO J 22:5435–5445PubMedCentralCrossRefPubMedGoogle Scholar
  35. Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13:89–102PubMedGoogle Scholar
  36. Hong, M., Li, M., Mao, C. & Lee, A.S., "Endoplasmic reticulum stress triggers an acute proteasome-dependent degradation of ATF6", Journal of cellular biochemistry, vol. 92, no. 4(2004a)723-732.Google Scholar
  37. Hong, M., Luo, S., Baumeister, P., Huang, J.M., Gogia, R.K., Li, M. & Lee, A.S., "Underglycosylation of ATF6 as a novel sensing mechanism for activation of the unfolded protein response", The Journal of biological chemistry, vol. 279, no. 12,(2004b)11354-11363.Google Scholar
  38. Hoozemans JJ, Veerhuis R, Van Haastert ES, Rozemuller JM, Baas F, Eikelenboom P, Scheper W (2005) The unfolded protein response is activated in Alzheimer’s disease. Acta Neuropathol 110:165e172CrossRefGoogle Scholar
  39. Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Eikelenboom P, Scheper W (2009) The unfolded protein response is activated in pretangleneurons in Alzheimer’s disease hippocampus. Am J Pathol 174:1241e1251CrossRefGoogle Scholar
  40. Kaufman RJ, Scheuner D, Schroder M, Shen X, Lee K, Liu CY et al (2002) The unfolded protein response in nutrient sensing and differentiation. Nat RevMolCell Biol 3:411–421CrossRefPubMedGoogle Scholar
  41. Kawaguchi T, Miyazawa K, Moriya S, Ohtomo T, Che XF, Naito M et al (2011) Combined treatment with bortezomi b plus bafilomycin A1enhances the cytocidal effect and induces endoplasmic reticulum stressin U266 myeloma cells:crosstalk among proteasome, autophagy lysosomeand ER stress. Int J Oncol 38:643–654PubMedGoogle Scholar
  42. Kim I, Xu W, Reed JC (2008) Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discovery 7:1013–1030CrossRefPubMedGoogle Scholar
  43. Kleizen B, Braakman I (2004) Protein folding and quality control in the endoplasmic reticulum. Current opinion in cell biology 16(4):343–349CrossRefPubMedGoogle Scholar
  44. Laitusis AL, Brostrom MA, Brostrom CO (1999) The dynamic role of GRP78/BiP in the coordination of mRNA translation with protein processing. The Journal of biological chemistry 274(1):486–493CrossRefPubMedGoogle Scholar
  45. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787e795CrossRefGoogle Scholar
  46. Lindholm D, Wootz H, Korhonen L (2006) ER stress and neurodegenerative diseases. Cell Death Differ 13:385–392CrossRefPubMedGoogle Scholar
  47. Merulla J, Fasana E, Solda T, Molinari M (2013) Specificity and regulation of the endoplasmic reticulum-associated degradation machinery. Traffic 14:767–777CrossRefPubMedGoogle Scholar
  48. Meusser B, Hirsch C, Jarosch E, Sommer T (2005) ERAD: the long road to destruction. Nat Cell Biol 7:766–772CrossRefPubMedGoogle Scholar
  49. Molinari M, Calanca V, Galli C, Lucca P, Paganetti P (2003) Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle. Science 299(5611):1397–1400CrossRefPubMedGoogle Scholar
  50. Molinari M, Galli C, Piccaluga V, Pieren M, Paganetti P (2002) Sequential assistance of molecular chaperones and transient formation of covalent complexes during protein degradation from the ER. J Cell Biol 158:247–257PubMedCentralCrossRefPubMedGoogle Scholar
  51. Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori CA et al (2012) Sustained translational repression by eIF2alpha-P mediates prion neurodegeneration. Nature 485:507e511Google Scholar
  52. Nguyen T, Huang HC, Pickett CB (2000) Transcriptional regulation of the antioxidant response element: activation by Nrf2 and repression byMafK. J Biol Chem 275:15466–15473CrossRefPubMedGoogle Scholar
  53. Nishitoh H et al (2008) ALS-linked mutant SOD1 induces ER stress- and ASK1- dependent motor neuron death by targeting Derlin-1. Genes Dev 22(11):1451–1464PubMedCentralCrossRefPubMedGoogle Scholar
  54. Novoa I, Zeng H, Harding HP, Ron D (2001) Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 153:1011–1022PubMedCentralCrossRefPubMedGoogle Scholar
  55. Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S et al (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol CellBiol 26:9220–9231PubMedCentralCrossRefPubMedGoogle Scholar
  56. Oyadomari S, Yun C, Fisher EA, Kreglinger N, Kreibich G, Oyadomari M et al (2006) Co translocational degradation protects the stressed endoplasmic reticulum from protein overload. Cell 126:727–739CrossRefPubMedGoogle Scholar
  57. Parmar VM, Schroder M (2012) Sensing endoplasmic reticulum stress. Adv Exp Med Biol 738:153–168CrossRefPubMedGoogle Scholar
  58. Rao RV, Bredesen DE (2004) Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. CurrentOpinionCell Biol 16:653–662PubMedCentralCrossRefPubMedGoogle Scholar
  59. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nature Reviews Molecular Cell Biology 8:519–529CrossRefPubMedGoogle Scholar
  60. Rubinsztein DC (2006) The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443:780e786CrossRefGoogle Scholar
  61. Saris N, Holkeri H, Craven RA, Stirling CJ, Makarow M (1997) The Hsp70 homologue Lhs1p is involved in a novel function of the yeast endoplasmic reticulum, refolding and stabilization of heat denatured protein aggregates. The Journal of cell biology 137(4):813–824PubMedCentralCrossRefPubMedGoogle Scholar
  62. Scheuner D, Song B, McEwen E, Liu C, Laybutt R, Gillespie P, Saunders T, Bonner-Weir S, Kaufman RJ (2001) Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Molecular cell 7(6):1165–1176CrossRefPubMedGoogle Scholar
  63. Schnell S (2009) A model of the unfolded protein response: pancreatic beta-cell as a case study. Cell PhysiolBiochem 23:233–244CrossRefPubMedGoogle Scholar
  64. Schroder M (2008) Endoplasmic reticulum stress responses. Cellular and molecular life sciences 65(6):862–894CrossRefPubMedGoogle Scholar
  65. Schroder, M., Kaufman, R.J. ER stress and the unfolded protein response. Mutat. Res. 569(2005a)29–63.Google Scholar
  66. Shen J, Chen X, Hendershot L, Prywes R (2002) ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Developmental cell 3(1):99–111CrossRefPubMedGoogle Scholar
  67. Sood R, Porter AC, Ma K, Quilliam LA, Wek RC (2000) Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress. The Biochemical journal 346(Pt 2):281–293PubMedCentralCrossRefPubMedGoogle Scholar
  68. Szegezdi E, Logue SE, Gorman AM, Samali A (2006) Mediators of endoplasmic reticulum stress induced apoptosis. EMBO Rep 7:880–885PubMedCentralCrossRefPubMedGoogle Scholar
  69. Tirasophon W, Welihinda AA, Kaufman RJ (1998) A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein 102 kinase/endoribonuclease (Ire1p) in mammalian cells. Genes & development 12(12):1812–1824CrossRefGoogle Scholar
  70. Torres M, Castillo K, Armisen R, Stutzin A, Soto C, Hetz C (2010) Prion protein misfolding affects calcium homeostasis and sensitizes cells to endoplasmic reticulum stress. PLoS One 5:e15658PubMedCentralCrossRefPubMedGoogle Scholar
  71. Van HR, Martindale JL, Gorospe M, Holbrook NJ (2003) P58IPK, a novel endoplasmic reticulum stress inducible protein and potential negative regulator of eIF2 alpha signaling. J BiolChem 278:15558–15564CrossRefGoogle Scholar
  72. Vasa-Nicotera M (2004) The new kid on the block: the unfolded protein response in the pathogenesis of atherosclerosis. Cell Death Differ 11(suppl1):S10–S11Google Scholar
  73. Wang XZ, Harding HP, Zhang Y, Jolicoeur EM, Kuroda M, Ron D (1998) Cloning of mammalian Ire1 reveals diversity in the ER stress responses. The EMBO journal 17(19):5708–5717PubMedCentralCrossRefPubMedGoogle Scholar
  74. Williams DB (2006) Beyond lectins: the calnexin/calreticulin chaperone system of the endoplasmic reticulum. Journal of cell science 119(Pt 4):615–623CrossRefPubMedGoogle Scholar
  75. Wimo A, Winblad B, Aguero-Torres H, von Strauss E (2003) The magnitude of dementia occurrence in the world. Alzheimer Dis Assoc Disord 17:63e67CrossRefGoogle Scholar
  76. Winter J, Jakob U (2004) Beyond transcription—new mechanisms for the regulation of molecular chaperones. Critical reviews in biochemistry and molecular biology 39(5-6):297–317CrossRefPubMedGoogle Scholar
  77. Yamamoto K, Yoshida H, Kokame K, Kaufman RJ, Mori K (2004) Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. Journal of Biochemistry 136(3):343–350CrossRefPubMedGoogle Scholar
  78. Yamamoto K, Sato T, Matsui T, Sato M, Okada T, Yoshida H (2007) Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6 alpha and XBP1. Dev Cell 13:365–376CrossRefPubMedGoogle Scholar
  79. Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T, Tohyama M (2001) Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor 105 necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. The Journal of biological chemistry 276(17):13935–13940PubMedGoogle Scholar
  80. Yoo BC, Krapfenbauer K, Cairns N, Belay G, Bajo M, Lubec G (2002) Over expressed protein disulfide isomerase in brains of patients with sporadic CreutzfeldteJakob disease. Neurosci Lett 334:196e200CrossRefGoogle Scholar
  81. Yorimitsu T, Nair U, Yang Z, Klionsky DJ (2006) Endoplasmic reticulum stress triggers autophagy. J BiolChem 281:30299–30304PubMedCentralCrossRefPubMedGoogle Scholar
  82. Yoshida H (2007) ER stress and diseases. FEBS J 274:630–658CrossRefPubMedGoogle Scholar
  83. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107(7):881–891CrossRefPubMedGoogle Scholar
  84. Zhao L, Ackerman SL (2006) Endoplasmic reticulum stress in health and disease. CurrOpinCell Biol 18:444–452CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Syed Zahid Ali Shah
    • 1
  • Deming Zhao
    • 1
  • Sher Hayat Khan
    • 1
  • Lifeng Yang
    • 1
    Email author
  1. 1.State Key Laboratories for Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary MedicineChina Agricultural UniversityBeijingChina

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