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Open Access 01-09-2015 | Review

The unfolded protein response in neurodegenerative diseases: a neuropathological perspective

Authors: Wiep Scheper, Jeroen J. M. Hoozemans

Published in: Acta Neuropathologica | Issue 3/2015

Abstract

The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER) to a disturbance in protein folding. The so-called ER stress sensors PERK, IRE1 and ATF6 play a central role in the initiation and regulation of the UPR. The accumulation of misfolded and aggregated proteins is a common characteristic of neurodegenerative diseases. With the discovery of the basic machinery of the UPR, the idea was born that the UPR or part of its machinery could be involved in neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and prion disease. Over the last decade, the UPR has been addressed in an increasing number of studies on neurodegeneration. The involvement of the UPR has been investigated in human neuropathology across different neurological diseases, as well as in cell and mouse models for neurodegeneration. Studies using different disease models display discrepancies on the role and function of the UPR during neurodegeneration, which can often be attributed to differences in methodology. In this review, we will address the importance of investigation of human brain material for the interpretation of the role of the UPR in neurological diseases. We will discuss evidence for UPR activation in neurodegenerative diseases, and the methodology to study UPR activation and its connection to brain pathology will be addressed. More recently, the UPR is recognized as a target for drug therapy for treatment and prevention of neurodegeneration, by inhibiting the function of specific mediators of the UPR. Several preclinical studies have shown a proof-of-concept for this approach targeting the machinery of UPR, in particular the PERK pathway, in different models for neurodegeneration and have yielded paradoxical results. The promises held by these observations will need further support by clarification of the observed differences between disease models, as well as increased insight obtained from human neuropathology.

Abisambra JF, Jinwal UK, Blair LJ, O’Leary JC III, Li Q, Brady S, Wang L, Guidi CE, Zhang B, Nordhues BA, Cockman M, Suntharalingham A, Li P, Jin Y, Atkins CA, Dickey CA (2013) Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. J Neurosci 33:9498–9507. doi:10.1523/JNEUROSCI.5397-12.2013 PubMedCentralPubMed

Atkin JD, Farg MA, Walker AK, McLean C, Tomas D, Horne MK (2008) Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis. Neurobiol Dis 30:400–407. doi:10.1016/j.nbd.2008.02.009 PubMed

Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, Li WH, Heerding DA, Minthorn E, Mencken T, Atkins C, Liu Q, Rabindran S, Kumar R, Hong X, Goetz A, Stanley T, Taylor JD, Sigethy SD, Tomberlin GH, Hassell AM, Kahler KM, Shewchuk LM, Gampe RT (2012) 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 55:7193–7207. doi:10.1021/jm300713s PubMed

Ball MJ, Lo P (1977) Granulovacuolar degeneration in the ageing brain and in dementia. J Neuropathol Exp Neurol 36:474–487PubMed

Bernales S, McDonald KL, Walter P (2006) Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol 4:e423PubMedCentralPubMed

Bernales S, Schuck S, Walter P (2007) ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy 3:285–287PubMed

Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, Yuan J (2005) A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 307:935–939PubMed

Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–59PubMed

Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211PubMed

10.

Bruijn LI, Miller TM, Cleveland DW (2004) Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci 27:723–749. doi:10.1146/annurev.neuro.27.070203.144244 PubMed

11.

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 415:92–96. doi:10.1038/415092a PubMed

12.

Carnemolla A, Fossale E, Agostoni E, Michelazzi S, Calligaris R, De ML, Del SG, MacDonald ME, Persichetti F (2009) Rrs1 is involved in endoplasmic reticulum stress response in Huntington disease. J Biol Chem 284:18167–18173. doi:10.1074/jbc.M109.018325 PubMedCentralPubMed

13.

Chafekar SM, Baas F, Scheper W (2008) Oligomer-specific Abeta toxicity in cell models is mediated by selective uptake. Biochim Biophys Acta 1782:523–531PubMed

14.

Chafekar SM, Hoozemans JJ, Zwart R, Baas F, Scheper W (2007) Abeta 1-42 induces mild endoplasmic reticulum stress in an aggregation state-dependent manner. Antioxid Redox Signal 9:2245–2254PubMed

15.

Chang RC, Suen KC, Ma CH, Elyaman W, Ng HK, Hugon J (2002) Involvement of double-stranded RNA-dependent protein kinase and phosphorylation of eukaryotic initiation factor-2alpha in neuronal degeneration. J Neurochem 83:1215–1225PubMed

16.

Chung CY, Khurana V, Auluck PK, Tardiff DF, Mazzulli JR, Soldner F, Baru V, Lou Y, Freyzon Y, Cho S, Mungenast AE, Muffat J, Mitalipova M, Pluth MD, Jui NT, Schule B, Lippard SJ, Tsai LH, Krainc D, Buchwald SL, Jaenisch R, Lindquist S (2013) Identification and rescue of alpha-synuclein toxicity in Parkinson patient-derived neurons. Science 342:983–987. doi:10.1126/science.1245296 PubMedCentralPubMed

17.

Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F, Cao S, Caldwell KA, Caldwell GA, Marsischky G, Kolodner RD, Labaer J, Rochet JC, Bonini NM, Lindquist S (2006) Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 313:324–328PubMedCentralPubMed

18.

Cox JS, Shamu CE, Walter P (1993) Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell 73:1197–1206PubMed

19.

Cox JS, Walter P (1996) A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response. Cell 87:391–404PubMed

20.

Cross BC, Bond PJ, Sadowski PG, Jha BK, Zak J, Goodman JM, Silverman RH, Neubert TA, Baxendale IR, Ron D, Harding HP (2012) The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc Natl Acad Sci 109:E869–E878. doi:10.1073/pnas.1115623109 PubMedCentralPubMed

21.

Das I, Krzyzosiak A, Schneider K, Wrabetz L, D’Antonio M, Barry N, Sigurdardottir A, Bertolotti A (2015) Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science 348:239–242. doi:10.1126/science.aaa4484 PubMed

22.

DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GY, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256. doi:10.1016/j.neuron.2011.09.011 PubMedCentralPubMed

23.

Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C (2000) EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 25:406–409. doi:10.1038/78085 PubMed

24.

Ding WX, Ni HM, Gao W, Hou YF, Melan MA, Chen X, Stolz DB, Shao ZM, Yin XM (2007) Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J Biol Chem 282:4702–4710PubMed

25.

Donnelly N, Gorman AM, Gupta S, Samali A (2013) The eIF2alpha kinases: their structures and functions. Cell Mol Life Sci 70:3493–3511. doi:10.1007/s00018-012-1252-6 PubMed

26.

Fernandez-Fernandez MR, Ferrer I, Lucas JJ (2011) Impaired ATF6alpha processing, decreased Rheb and neuronal cell cycle re-entry in Huntington’s disease. Neurobiol Dis 41:23–32. doi:10.1016/j.nbd.2010.08.014 PubMed

27.

Ghosh R, Wang L, Wang ES, Perera BG, Igbaria A, Morita S, Prado K, Thamsen M, Caswell D, Macias H, Weiberth KF, Gliedt MJ, Alavi MV, Hari SB, Mitra AK, Bhhatarai B, Schurer SC, Snapp EL, Gould DB, German MS, Backes BJ, Maly DJ, Oakes SA, Papa FR (2014) Allosteric inhibition of the IRE1alpha RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158:534–548. doi:10.1016/j.cell.2014.07.002 PubMedCentralPubMed

28.

Halliday M, Radford H, Sekine Y, Moreno J, Verity N, le Quesne J, Ortori CA, Barrett DA, Fromont C, Fischer PM, Harding HP, Ron D, Mallucci GR (2015) Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis. doi:10.1038/cddis.2015.49 PubMedCentralPubMed

29.

Hamos JE, Oblas B, Pulaski-Salo D, Welch WJ, Bole DG, Drachman DA (1991) Expression of heat shock proteins in Alzheimer’s disease. Neurology 41:345–350PubMed

30.

Han D, Lerner AG, Vande WL, Upton JP, Xu W, Hagen A, Backes BJ, Oakes SA, Papa FR (2009) IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138:562–575. doi:10.1016/j.cell.2009.07.017 PubMedCentralPubMed

31.

Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD, Ron D (2001) Diabetes mellitus and exocrine pancreatic dysfunction in perk−/− mice reveals a role for translational control in secretory cell survival. Mol Cell 7:1153–1163PubMed

32.

Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5:897–904PubMed

33.

Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397:271–274. doi:10.1038/16729 PubMed

34.

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. Mol Biol Cell 10:3787–3799PubMedCentralPubMed

35.

Hetz C, Glimcher LH (2009) Fine-tuning of the unfolded protein response: assembling the IRE1alpha interactome. Mol Cell 35:551–561. doi:10.1016/j.molcel.2009.08.021 PubMedCentralPubMed

36.

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 22:5435–5445PubMedCentralPubMed

37.

Hetz C, Thielen P, Matus S, Nassif M, Court F, Kiffin R, Martinez G, Cuervo AM, Brown RH, Glimcher LH (2009) XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev 23:2294–2306. doi:10.1101/gad.1830709 PubMedCentralPubMed

38.

Ho YS, Yang X, Lau JC, Hung CH, Wuwongse S, Zhang Q, Wang J, Baum L, So KF, Chang RC (2012) Endoplasmic reticulum stress induces tau pathology and forms a vicious cycle: implication in Alzheimer’s disease pathogenesis. J Alzheimers Dis 28:839–854. doi:10.3233/JAD-2011-111037 PubMed

39.

Höglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L, Rademakers R, de Silva R, Litvan I, Riley DE, van Swieten JC, Heutink P, Wszolek ZK, Uitti RJ, Vandrovcova J, Hurtig HI, Gross RG, Maetzler W, Goldwurm S, Tolosa E, Borroni B, Pastor P, PSP Genetics Study Group, Cantwell LB, Han MR, Dillman A, van der Brug MP, Gibbs JR, Cookson MR, Hernandez DG, Singleton AB, Farrer MJ, Yu CE, Golbe LI, Revesz T, Hardy J, Lees AJ, Devlin B, Hakonarson H, Müller U, Schellenberg GD (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43:699–705. doi:10.1038/ng.859

40.

Hoozemans JJ, Van Haastert ES, Eikelenboom P, de Vos RA, Rozemuller JM, Scheper W (2007) Activation of the unfolded protein response in Parkinson’s disease. Biochem Biophys Res Commun 354:707–711PubMed

41.

Hoozemans JJ, Van Haastert ES, Nijholt DA, Rozemuller AJ, Eikelenboom P, Scheper W (2009) The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am J Pathol 174:1241–1251. doi:10.2353/ajpath.2009.080814 PubMedCentralPubMed

42.

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 (Berl) 110:165–172

43.

Hou HL, Shen YX, Zhu HY, Sun H, Yan XB, Fang H, Zhou JN (2006) Alterations of hHrd1 expression are related to hyperphosphorylated tau in the hippocampus in Alzheimer’s disease. J Neurosci Res 84:1862–1870. doi:10.1002/jnr.21081 PubMed

44.

Ilieva EV, Ayala V, Jove M, Dalfo E, Cacabelos D, Povedano M, Bellmunt MJ, Ferrer I, Pamplona R, Portero-Otin M (2007) Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis. Brain 130:3111–3123. doi:10.1093/brain/awm190 PubMed

45.

Ito Y, Yamada M, Tanaka H, Aida K, Tsuruma K, Shimazawa M, Hozumi I, Inuzuka T, Takahashi H, Hara H (2009) Involvement of CHOP, an ER-stress apoptotic mediator, in both human sporadic ALS and ALS model mice. Neurobiol Dis 36:470–476. doi:10.1016/j.nbd.2009.08.013 PubMed

46.

Iwakoshi NN, Lee AH, Vallabhajosyula P, Otipoby KL, Rajewsky K, Glimcher LH (2003) Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol 4:321–329. doi:10.1038/ni907 PubMed

47.

Kakiuchi C, Iwamoto K, Ishiwata M, Bundo M, Kasahara T, Kusumi I, Tsujita T, Okazaki Y, Nanko S, Kunugi H, Sasaki T, Kato T (2003) Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nat Genet 35:171–175. doi:10.1038/ng1235 PubMed

48.

Katayama T, Imaizumi K, Sato N, Miyoshi K, Kudo T, Hitomi J, Morihara T, Yoneda T, Gomi F, Mori Y, Nakano Y, Takeda J, Tsuda T, Itoyama Y, Murayama O, Takashima A, St George-Hyslop P, Takeda M, Tohyama M (1999) Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Nat Cell Biol 1:479–485PubMed

49.

Kiskinis E, Sandoe J, Williams LA, Boulting GL, Moccia R, Wainger BJ, Han S, Peng T, Thams S, Mikkilineni S, Mellin C, Merkle FT, Davis-Dusenbery BN, Ziller M, Oakley D, Ichida J, Di CS, Atwater N, Maeder ML, Goodwin MJ, Nemesh J, Handsaker RE, Paull D, Noggle S, McCarroll SA, Joung JK, Woolf CJ, Brown RH, Eggan K (2014) Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1. Cell Stem Cell 14:781–795. doi:10.1016/j.stem.2014.03.004 PubMed

50.

Kohler C, Dinekov M, Gotz J (2014) Granulovacuolar degeneration and unfolded protein response in mouse models of tauopathy and Abeta amyloidosis. Neurobiol Dis 71:169–179. doi:10.1016/j.nbd.2014.07.006 PubMed

51.

Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K, Egawa N, Yahata N, Okita K, Takahashi K, Asaka I, Aoi T, Watanabe A, Watanabe K, Kadoya C, Nakano R, Watanabe D, Maruyama K, Hori O, Hibino S, Choshi T, Nakahata T, Hioki H, Kaneko T, Naitoh M, Yoshikawa K, Yamawaki S, Suzuki S, Hata R, Ueno S, Seki T, Kobayashi K, Toda T, Murakami K, Irie K, Klein WL, Mori H, Asada T, Takahashi R, Iwata N, Yamanaka S, Inoue H (2013) Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell 12:487–496. doi:10.1016/j.stem.2013.01.009 PubMed

52.

Kozutsumi Y, Segal M, Normington K, Gething MJ, Sambrook J (1988) The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature 332:462–464. doi:10.1038/332462a0 PubMed

53.

Lee AS (1987) Coordinated regulation of a set of genes by glucose and calcium ionophores in mammalian cells. Trends Biochem Sci 12:20–23

54.

Lee H, Noh JY, Oh Y, Kim Y, Chang JW, Chung CW, Lee ST, Kim M, Ryu H, Jung YK (2012) IRE1 plays an essential role in ER stress-mediated aggregation of mutant huntingtin via the inhibition of autophagy flux. Hum Mol Genet 21:101–114. doi:10.1093/hmg/ddr445 PubMed

55.

Lee K, Tirasophon W, Shen X, Michalak M, Prywes R, Okada T, Yoshida H, Mori K, Kaufman RJ (2002) IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev 16:452–466PubMedCentralPubMed

56.

Lin L, Yang SS, Chu J, Wang L, Ning LN, Zhang T, Jiang Q, Tian Q, Wang JZ (2014) Region-specific expression of tau, amyloid-beta protein precursor, and synaptic proteins at physiological condition or under endoplasmic reticulum stress in rats. J Alzheimers Dis. doi:10.3233/JAD-140207 (831M243753684PJJ)

57.

Liu J, Hoppman N, O’Connell JR, Wang H, Streeten EA, McLenithan JC, Mitchell BD, Shuldiner AR (2012) A functional haplotype in EIF2AK3, an ER stress sensor, is associated with lower bone mineral density. J Bone Miner Res 27:331–341. doi:10.1002/jbmr.549 PubMedCentralPubMed

58.

Liu QY, Yu JT, Miao D, Ma XY, Wang HF, Wang W, Tan L (2013) An exploratory study on STX6, MOBP, MAPT, and EIF2AK3 and late-onset Alzheimer’s disease. Neurobiol Aging 34:1519.e13–1519.e17. doi:10.1016/j.neurobiolaging.2012.10.004

59.

Liu SY, Wang W, Cai ZY, Lao LF, Chen ZW, Wang CY, Zhao B, Li KS (2013) Polymorphism-116C/G of human X-box-binding protein 1 promoter is associated with risk of Alzheimer’s disease. CNS Neurosci Ther. doi:10.1111/cns.12064 PubMedCentral

60.

Ma T, Trinh MA, Wexler AJ, Bourbon C, Gatti E, Pierre P, Cavener DR, Klann E (2013) Suppression of eIF2alpha kinases alleviates Alzheimer’s disease-related plasticity and memory deficits. Nat Neurosci 16:1299–1305. doi:10.1038/nn.3486 PubMedCentralPubMed

61.

Makioka K, Yamazaki T, Fujita Y, Takatama M, Nakazato Y, Okamoto K (2010) Involvement of endoplasmic reticulum stress defined by activated unfolded protein response in multiple system atrophy. J Neurol Sci 297:60–65. doi:10.1016/j.jns.2010.06.019 PubMed

62.

Maly DJ, Papa FR (2014) Druggable sensors of the unfolded protein response. Nat Chem Biol 10:892–901. doi:10.1038/nchembio.1664 PubMed

63.

Maurel M, McGrath EP, Mnich K, Healy S, Chevet E, Samali A (2015) Controlling the unfolded protein response-mediated life and death decisions in cancer. Semin Cancer Biol. doi:10.1016/j.semcancer.2015.03.003 PubMed

64.

Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, Ortori CA, Willis AE, Fischer PM, Barrett DA, Mallucci GR (2013) Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med 5:206ra138. doi:10.1126/scitranslmed.3006767 (-5/206/206ra138)

65.

Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, Bushell M, Mallucci GR (2012) Sustained translational repression by eIF2alpha-P mediates prion neurodegeneration. Nature 485:507–511. doi:10.1038/nature11058 PubMedCentralPubMed

66.

Mori K, Ma W, Gething MJ, Sambrook J (1993) A transmembrane protein with a cdc2+/CDC28-related kinase activity is required for signaling from the ER to the nucleus. Cell 74:743–756PubMed

67.

Mori K, Sant A, Kohno K, Normington K, Gething MJ, Sambrook JF (1992) A 22 bp cis-acting element is necessary and sufficient for the induction of the yeast KAR2 (BiP) gene by unfolded proteins. EMBO J 11:2583–2593PubMedCentralPubMed

68.

Nagata T, Ilieva H, Murakami T, Shiote M, Narai H, Ohta Y, Hayashi T, Shoji M, Abe K (2007) Increased ER stress during motor neuron degeneration in a transgenic mouse model of amyotrophic lateral sclerosis. Neurol Res 29:767–771. doi:10.1179/016164107X229803 PubMed

69.

Nijholt DA, de Graaf TR, Van Haastert ES, Oliveira AO, Berkers CR, Zwart R, Ovaa H, Baas F, Hoozemans JJ, Scheper W (2011) Endoplasmic reticulum stress activates autophagy but not the proteasome in neuronal cells: implications for Alzheimer’s disease. Cell Death Differ 18:1071–1081. doi:10.1038/cdd.2010.176 PubMedCentralPubMed

70.

Nijholt DA, Van Haastert ES, Rozemuller AJ, Scheper W, Hoozemans JJ (2012) The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies. J Pathol 226:693–702. doi:10.1002/path.3969 PubMed

71.

Niwa M, Sidrauski C, Kaufman RJ, Walter P (1999) A role for presenilin-1 in nuclear accumulation of Ire1 fragments and induction of the mammalian unfolded protein response. Cell 99:691–702PubMed

72.

O’Connor T, Sadleir KR, Maus E, Velliquette RA, Zhao J, Cole SL, Eimer WA, Hitt B, Bembinster LA, Lammich S, Lichtenthaler SF, Hebert SS, De Strooper B, Haass C, Bennett DA, Vassar R (2008) Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron 60:988–1009PubMedCentralPubMed

73.

Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F, Imaizumi K (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26:9220–9231PubMedCentralPubMed

74.

Okamoto K, Hirai S, Iizuka T, Yanagisawa T, Watanabe M (1991) Reexamination of granulovacuolar degeneration. Acta Neuropathol 82:340–345PubMed

75.

Piccini A, Fassio A, Pasqualetto E, Vitali A, Borghi R, Palmieri D, Nacmias B, Sorbi S, Sitia R, Tabaton M (2004) Fibroblasts from FAD-linked presenilin 1 mutations display a normal unfolded protein response but overproduce Abeta42 in response to tunicamycin. Neurobiol Dis 15:380–386PubMed

76.

Reimold AM, Etkin A, Clauss I, Perkins A, Friend DS, Zhang J, Horton HF, Scott A, Orkin SH, Byrne MC, Grusby MJ, Glimcher LH (2000) An essential role in liver development for transcription factor XBP-1. Genes Dev 14:152–157PubMedCentralPubMed

77.

Ren Y, Yang S, Xu S, Gao M, Huang W, Gao T, Fang Q, Quan C, Zhang C, Sun L, Liang Y, Han J, Wang Z, Zhang F, Zhou Y, Liu J, Zhang X (2009) Genetic variation of promoter sequence modulates XBP1 expression and genetic risk for vitiligo. PLoS Genet 5:e1000523. doi:10.1371/journal.pgen.1000523 PubMedCentralPubMed

78.

Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister JB, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls MA, Peuralinna T, Jansson L, Isoviita VM, Kaivorinne AL, Holtta-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chio A, Restagno G, Borghero G, Sabatelli M, Heckerman D, Rogaeva E, Zinman L, Rothstein JD, Sendtner M, Drepper C, Eichler EE, Alkan C, Abdullaev Z, Pack SD, Dutra A, Pak E, Hardy J, Singleton A, Williams NM, Heutink P, Pickering-Brown S, Morris HR, Tienari PJ, Traynor BJ (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268. doi:10.1016/j.neuron.2011.09.010 PubMedCentralPubMed

79.

Roussel BD, Kruppa AJ, Miranda E, Crowther DC, Lomas DA, Marciniak SJ (2013) Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol 12:105–118. doi:10.1016/S1474-4422(12)70238-7 PubMed

80.

Ruggiano A, Foresti O, Carvalho P (2014) Quality control: ER-associated degradation: protein quality control and beyond. J Cell Biol 204:869–879. doi:10.1083/jcb.201312042 PubMedCentralPubMed

81.

Rutkowski DT, Hegde RS (2010) Regulation of basal cellular physiology by the homeostatic unfolded protein response. J Cell Biol 189:783–794. doi:10.1083/jcb.201003138 PubMedCentralPubMed

82.

Ryu EJ, Harding HP, Angelastro JM, Vitolo OV, Ron D, Greene LA (2002) Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson’s disease. J Neurosci 22:10690–10698PubMed

83.

Saleh M, Mathison JC, Wolinski MK, Bensinger SJ, Fitzgerald P, Droin N, Ulevitch RJ, Green DR, Nicholson DW (2006) Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice. Nature 440:1064–1068. doi:10.1038/nature04656 PubMed

84.

Saleh M, Vaillancourt JP, Graham RK, Huyck M, Srinivasula SM, Alnemri ES, Steinberg MH, Nolan V, Baldwin CT, Hotchkiss RS, Buchman TG, Zehnbauer BA, Hayden MR, Farrer LA, Roy S, Nicholson DW (2004) Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature 429:75–79. doi:10.1038/nature02451 PubMed

85.

Sanches M, Duffy NM, Talukdar M, Thevakumaran N, Chiovitti D, Canny MD, Lee K, Kurinov I, Uehling D, Al-awar R, Poda G, Prakesch M, Wilson B, Tam V, Schweitzer C, Toro A, Lucas JL, Vuga D, Lehmann L, Durocher D, Zeng Q, Patterson JB, Sicheri F (2014) Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors. Nat Commun 5:4202. doi:10.1038/ncomms5202 PubMedCentralPubMed

86.

Sasaki S (2010) Endoplasmic reticulum stress in motor neurons of the spinal cord in sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 69:346–355. doi:10.1097/NEN.0b013e3181d44992 PubMed

87.

Sato N, Urano F, Yoon Leem J, Kim SH, Li M, Donoviel D, Bernstein A, Lee AS, Ron D, Veselits ML, Sisodia SS, Thinakaran G (2000) Upregulation of BiP and CHOP by the unfolded-protein response is independent of presenilin expression. Nat Cell Biol 2:863–870PubMed

88.

Saxena S, Cabuy E, Caroni P (2009) A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat Neurosci 12:627–636. doi:10.1038/nn.2297 PubMed

89.

Scheper W, Hoozemans JJ (2013) A new PERKspective on neurodegeneration. Sci Transl Med 5:206fs37. doi:10.1126/scitranslmed.3007641 (-5/206/206fs37)

90.

Scheper W, Nijholt DA, Hoozemans JJ (2011) The unfolded protein response and proteostasis in Alzheimer disease: preferential activation of autophagy by endoplasmic reticulum stress. Autophagy 7:910–911PubMedCentralPubMed

91.

Scheuner D, Kaufman RJ (2008) The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes. Endocr Rev 29:317–333. doi:10.1210/er.2007-0039 PubMedCentralPubMed

92.

Schwenk BM, Edbauer D (2014) The ER under rapid fire. EMBO J 33:1195–1197. doi:10.1002/embj.201488692 PubMedCentralPubMed

93.

Sekine Y, Zyryanova A, Crespillo-Casado A, Fischer PM, Harding HP, Ron D (2015) Mutations in a translation initiation factor identify the target of a memory-enhancing compound. Science 348:1027–1030. doi:10.1126/science.aaa6986 PubMed

94.

Shamu CE, Walter P (1996) Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J 15:3028–3039PubMedCentralPubMed

95.

Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L, Wek RC (1998) Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol 18:7499–7509PubMedCentralPubMed

96.

Sidrauski C, Acosta-Alvear D, Khoutorsky A, Vedantham P, Hearn BR, Li H, Gamache K, Gallagher CM, Ang KK, Wilson C, Okreglak V, Ashkenazi A, Hann B, Nader K, Arkin MR, Renslo AR, Sonenberg N, Walter P (2013) Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife 2:e00498. doi:10.7554/eLife.00498

97.

Sidrauski C, McGeachy AM, Ingolia NT, Walter P (2015) The small molecule ISRIB reverses the effects of eIF2alpha phosphorylation on translation and stress granule assembly. eLife 4: 05033. doi:10.7554/eLife.05033

98.

Sidrauski C, Walter P (1997) The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell 90:1031–1039PubMed

99.

Srikanth NS, Seth PK (1990) Alterations in xenobiotic metabolizing enzymes in brain and liver of rats coexposed to endosulfan and malathion. J Appl Toxicol 10:157–160PubMed

100.

Stefanis L, Larsen KE, Rideout HJ, Sulzer D, Greene LA (2001) Expression of A53T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci 21:9549–9560PubMed

101.

Steiner H, Winkler E, Shearman MS, Prywes R, Haass C (2001) Endoproteolysis of the ER stress transducer ATF6 in the presence of functionally inactive presenilins. Neurobiol Dis 8:717–722PubMed

102.

Stoveken BJ (2013) Tau pathology as a cause and consequence of the UPR. J Neurosci 33:14285–14287. doi:10.1523/JNEUROSCI.2961-13.2013 PubMed

103.

Stutzbach LD, Xie SX, Naj AC, Albin R, Gilman S, Lee VM, Trojanowski JQ, Devlin B, Schellenberg GD (2013) The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease. Acta Neuropathol Commun 1:31. doi:10.1186/2051-5960-1-31 (-2051-5960-1-31)

104.

Subjeck JR, Shyy TT (1986) Stress protein systems of mammalian cells. Am J Physiol 250:C1–C17PubMed

105.

Suen KC, Lin KF, Elyaman W, So KF, Chang RC, Hugon J (2003) Reduction of calcium release from the endoplasmic reticulum could only provide partial neuroprotection against beta-amyloid peptide toxicity. J Neurochem 87:1413–1426PubMed

106.

Taylor JP, Hardy J, Fischbeck KH (2002) Toxic proteins in neurodegenerative disease. Science 296:1991–1995PubMed

107.

Thal DR, Del TK, Ludolph AC, Hoozemans JJ, Rozemuller AJ, Braak H, Knippschild U (2011) Stages of granulovacuolar degeneration: their relation to Alzheimer’s disease and chronic stress response. Acta Neuropathol 122:577–589. doi:10.1007/s00401-011-0871-6 PubMed

108.

Thal DR, Walter J, Saido TC, Fandrich M (2015) Neuropathology and biochemistry of Abeta and its aggregates in Alzheimer’s disease. Acta Neuropathol 129:167–182. doi:10.1007/s00401-014-1375-y PubMed

109.

Tirasophon W, Welihinda AA, Kaufman RJ (1998) A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev 12:1812–1824PubMedCentralPubMed

110.

Tsaytler P, Harding HP, Ron D, Bertolotti A (2011) Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science 332:91–94. doi:10.1126/science.1201396 PubMed

111.

Unterberger U, Hoftberger R, Gelpi E, Flicker H, Budka H, Voigtlander T (2006) Endoplasmic reticulum stress features are prominent in Alzheimer disease but not in prion diseases in vivo. J Neuropathol Exp Neurol 65:348–357PubMed

112.

Vaccaro A, Patten SA, Aggad D, Julien C, Maios C, Kabashi E, Drapeau P, Parker JA (2013) Pharmacological reduction of ER stress protects against TDP-43 neuronal toxicity in vivo. Neurobiol Dis 55:64–75. doi:10.1016/j.nbd.2013.03.015 PubMed

113.

van der Harg JM, Nölle A, Zwart R, Boerema AS, Van Haastert ES, Strijkstra AM, Hoozemans JJ, Scheper W (2014) The unfolded protein response mediates reversible tau phosphorylation induced by metabolic stress. Cell Death Dis 5:e1393. doi:10.1038/cddis.2014.354 PubMedCentralPubMed

114.

Vidal RL, Figueroa A, Court FA, Thielen P, Molina C, Wirth C, Caballero B, Kiffin R, Segura-Aguilar J, Cuervo AM, Glimcher LH, Hetz C (2012) Targeting the UPR transcription factor XBP1 protects against Huntington’s disease through the regulation of FoxO1 and autophagy. Hum Mol Genet 21:2245–2262. doi:10.1093/hmg/dds040 PubMedCentralPubMed

115.

Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SS, Sandoe J, Perez NP, Williams LA, Lee S, Boulting G, Berry JD, Brown RH Jr, Cudkowicz ME, Bean BP, Eggan K, Woolf CJ (2014) Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep 7:1–11. doi:10.1016/j.celrep.2014.03.019 PubMedCentralPubMed

116.

Wang J, Kang R, Huang H, Xi X, Wang B, Wang J, Zhao Z (2014) Hepatitis C virus core protein activates autophagy through EIF2AK3 and ATF6 UPR pathway-mediated MAP1LC3B and ATG12 expression. Autophagy 10:766–784. doi:10.4161/auto.27954 PubMed

117.

Wang L, Perera BG, Hari SB, Bhhatarai B, Backes BJ, Seeliger MA, Schurer SC, Oakes SA, Papa FR, Maly DJ (2012) Divergent allosteric control of the IRE1alpha endoribonuclease using kinase inhibitors. Nat Chem Biol 8:982–989. doi:10.1038/nchembio.1094 PubMedCentralPubMed

118.

Wang L, Popko B, Tixier E, Roos RP (2014) Guanabenz, which enhances the unfolded protein response, ameliorates mutant SOD1-induced amyotrophic lateral sclerosis. Neurobiol Dis 71:317–324. doi:10.1016/j.nbd.2014.08.010 PubMed

119.

Wang XZ, Harding HP, Zhang Y, Jolicoeur EM, Kuroda M, Ron D (1998) Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J 17:5708–5717. doi:10.1093/emboj/17.19.5708 PubMedCentralPubMed

120.

Welihinda AA, Kaufman RJ (1996) The unfolded protein response pathway in Saccharomyces cerevisiae. Oligomerization and trans-phosphorylation of Ire1p (Ern1p) are required for kinase activation. J Biol Chem 271:18181–18187PubMed

121.

Wu J, Rutkowski DT, Dubois M, Swathirajan J, Saunders T, Wang J, Song B, Yau GD, Kaufman RJ (2007) ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell 13:351–364. doi:10.1016/j.devcel.2007.07.005 PubMed

122.

Xu M, Shibayama H, Kobayashi H, Yamada K, Ishihara R, Zhao P, Takeuchi T, Yoshida K, Inagaki T, Nokura K (1992) Granulovacuolar degeneration in the hippocampal cortex of aging and demented patients–a quantitative study. Acta Neuropathol 85:1–9PubMed

123.

Yamamoto K, Sato T, Matsui T, Sato M, Okada T, Yoshida H, Harada A, Mori K (2007) Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev Cell 13:365–376. doi:10.1016/j.devcel.2007.07.018 PubMed

124.

Yamamoto K, Takahara K, Oyadomari S, Okada T, Sato T, Harada A, Mori K (2010) Induction of liver steatosis and lipid droplet formation in ATF6alpha-knockout mice burdened with pharmacological endoplasmic reticulum stress. Mol Biol Cell 21:2975–2986. doi:10.1091/mbc.E09-02-0133 PubMedCentralPubMed

125.

Yoshida H, Haze K, Yanagi H, Yura T, Mori K (1998) Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem 273:33741–33749PubMed

126.

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 107:881–891PubMed

127.

Yu Z, Luo H, Fu W, Mattson MP (1999) The endoplasmic reticulum stress-responsive protein GRP78 protects neurons against excitotoxicity and apoptosis: suppression of oxidative stress and stabilization of calcium homeostasis. Exp Neurol 155:302–314PubMed

128.

Zhang K, Wong HN, Song B, Miller CN, Scheuner D, Kaufman RJ (2005) The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. J Clin Invest 115:268–281. doi:10.1172/JCI21848 PubMedCentralPubMed

129.

Zhang P, McGrath B, Li S, Frank A, Zambito F, Reinert J, Gannon M, Ma K, McNaughton K, Cavener DR (2002) 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 22:3864–3874PubMedCentralPubMed

130.

Zhang YJ, Jansen-West K, Xu YF, Gendron TF, Bieniek KF, Lin WL, Sasaguri H, Caulfield T, Hubbard J, Daughrity L, Chew J, Belzil VV, Prudencio M, Stankowski JN, Castanedes-Casey M, Whitelaw E, Ash PE, DeTure M, Rademakers R, Boylan KB, Dickson DW, Petrucelli L (2014) Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol 128:505–524. doi:10.1007/s00401-014-1336-5 PubMedCentralPubMed

Title: The unfolded protein response in neurodegenerative diseases: a neuropathological perspective
Authors: Wiep Scheper
Jeroen J. M. Hoozemans
Publication date: 01-09-2015
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 3/2015
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-015-1462-8

At a glance: The STEP trials

Springer Medicine

The unfolded protein response in neurodegenerative diseases: a neuropathological perspective

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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