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ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis

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Abstract

Several theories on the pathomechanism of amyotrophic lateral sclerosis (ALS) have been proposed: misfolded protein aggregates, mitochondrial dysfunction, increased glutamate toxicity, increased oxidative stress, disturbance of intracellular trafficking, and so on. In parallel, a number of drugs that have been developed to alleviate the putative key pathomechanism of ALS have been under clinical trials. Unfortunately, however, almost all studies have finished unsuccessfully. This fact indicates that the key ALS pathomechanism still remains a tough enigma. Recent studies with autopsied ALS patients and studies using mutant SOD1 (mSOD1) transgenic mice have suggested that endoplasmic reticulum (ER) stress-related toxicity may be a relevant ALS pathomechanism. Levels of ER stress-related proteins were upregulated in motor neurons in the spinal cords of ALS patients. It was also shown that mSOD1, translocated to the ER, caused ER stress in neurons in the spinal cord of mSOD1 transgenic mice. We recently reported that the newly identified ALS-causative gene, vesicle-associated membrane protein-associated protein B (VAPB), plays a pivotal role in unfolded protein response (UPR), a physiological reaction against ER stress. The ALS-linked P56S mutation in VAPB nullifies the function of VAPB, resulting in motoneuronal vulnerability to ER stress. In this review, we summarize recent advances in research on the ALS pathomechanism especially addressing the putative involvement of ER stress and UPR dysfunction.

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References

  1. Bruijn LI et al (2004) Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci 27:723–749

    Article  PubMed  CAS  Google Scholar 

  2. Kato S et al (1999) Recent advances in research on neuropathological aspects of familial amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations: neuronal Lewy body-like hyaline inclusions and astrocytic hyaline inclusions. Histol Histopathol 14:973–989

    PubMed  CAS  Google Scholar 

  3. Toyoshima I et al (1989) Phosphorylation of neurofilament proteins and localization of axonal swellings in motor neuron disease. J Neurol Sci 89:269–277

    Article  PubMed  CAS  Google Scholar 

  4. Nakano I, Hirano A (1987) Atrophic cell processes of large motor neurons in the anterior horn in amyotrophic lateral sclerosis: observation with silver impregnation method. J Neuropathol Exp Neurol 46:40–49

    Article  PubMed  CAS  Google Scholar 

  5. Mourelatos Z et al (1994) Fragmentation of the Golgi apparatus of motor neurons in amyotrophic lateral sclerosis revealed by organelle-specific antibodies. Am J Pathol 144:1288–1300

    PubMed  CAS  Google Scholar 

  6. Kawahara Y et al (2004) Glutamate receptors: RNA editing and death of motor neurons. Nature 427:801

    Article  PubMed  CAS  Google Scholar 

  7. Niebroj-Dobosz I et al (2006) Auto-antibodies against proteins of spinal cord cells in cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). Folia Neuropathol 44:191–196

    PubMed  CAS  Google Scholar 

  8. Yasui M et al (1992) Magnesium and calcium contents in CNS tissues of amyotrophic lateral sclerosis patients from the Kii peninsula, Japan. Eur Neurol 32:95–98

    Article  PubMed  CAS  Google Scholar 

  9. Cox PA et al (2003) Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. Proc Natl Acad Sci USA 100:13380–13383

    Article  CAS  Google Scholar 

  10. Kurtzke JF et al (1982) Epidemiology of amyotrophic lateral sclerosis. Adv Neurol 36:281–302

    PubMed  CAS  Google Scholar 

  11. Horner RD et al (2003) Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology 61:742–749

    PubMed  CAS  Google Scholar 

  12. Rosen DR et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62, (Erratum in: Nature 364:362)

    Article  PubMed  CAS  Google Scholar 

  13. Yang Y et al (2001) The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet 29:160–165

    Article  PubMed  CAS  Google Scholar 

  14. Hadano S et al (2001) A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 29:166–173

    Article  PubMed  CAS  Google Scholar 

  15. Chen YZ et al (2004) DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 74:1128–1135

    Article  PubMed  CAS  Google Scholar 

  16. Nishimura AL et al (2004) A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 75:822–831

    Article  PubMed  CAS  Google Scholar 

  17. Münch C et al (2005) Heterozygous R1101K mutation of the DCTN1 gene in a family with ALS and FTD. Ann Neurol 58:777–780

    Article  PubMed  CAS  Google Scholar 

  18. Greenway MJ et al (2006) ANG mutations segregate with familial and ‘sporadic’ amyotrophic lateral sclerosis. Nat Genet 38:411–413

    Article  PubMed  CAS  Google Scholar 

  19. Sreedharan J et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672

    Article  PubMed  CAS  Google Scholar 

  20. Johnston JA et al (2000) Formation of high molecular weight complexes of mutant Cu, Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 97:12571–12576

    Article  PubMed  CAS  Google Scholar 

  21. Niwa J et al (2002) Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity. J Biol Chem 277:36793–36798

    Article  PubMed  CAS  Google Scholar 

  22. Liochev SI, Fridovich I (2003) Mutant Cu,Zn superoxide dismutases and familial amyotrophic lateral sclerosis: evaluation of oxidative hypotheses. Free Radic Biol Med 34:1383–1389

    Article  PubMed  CAS  Google Scholar 

  23. Deng HX et al (1993) Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science 261:1047–1051

    Article  PubMed  CAS  Google Scholar 

  24. Bowling AC et al (1995) Superoxide dismutase concentration and activity in familial amyotrophic lateral sclerosis. J Neurochem 64:2366–2369

    Article  PubMed  CAS  Google Scholar 

  25. Borchelt DR et al (1994) Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity. Proc Natl Acad Sci USA 91:8292–8296

    Article  PubMed  CAS  Google Scholar 

  26. Reaume AG et al (1996) Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 13:43–47

    Article  PubMed  CAS  Google Scholar 

  27. Gurney ME et al (1994) Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264:1772–1775, (Erratum in: Science 269:149)

    Article  PubMed  CAS  Google Scholar 

  28. Kato S et al (1996) Familial amyotrophic lateral sclerosis with a two base pair deletion in superoxide dismutase 1: gene multisystem degeneration with intracytoplasmic hyaline inclusions in astrocytes. J Neuropathol Exp Neurol 55:1089–1101

    Article  PubMed  CAS  Google Scholar 

  29. Bruijn LI et al (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18:327–338

    Article  PubMed  CAS  Google Scholar 

  30. Becher MW et al (1998) Intranuclear neuronal inclusions in Huntington’s disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol Dis 4:387–397

    Article  PubMed  CAS  Google Scholar 

  31. Trojanowski JQ, Lee VM (1998) Aggregation of neurofilament and alpha-synuclein proteins in Lewy bodies: implications for the pathogenesis of Parkinson disease and Lewy body dementia. Arch Neurol 55:151–152

    Article  PubMed  CAS  Google Scholar 

  32. Urushitani M et al (2002) Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosis. J Neurochem 83:1030–1042

    Article  PubMed  CAS  Google Scholar 

  33. Liu D et al (1999) The roles of free radicals in amyotrophic lateral sclerosis: reactive oxygen species and elevated oxidation of protein, DNA, and membrane phospholipids. FASEB J 13:2318–2328

    PubMed  CAS  Google Scholar 

  34. Pasinelli P et al (2004) Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron 43:19–30

    Article  PubMed  CAS  Google Scholar 

  35. Goldsteins G et al (2008) Deleterious role of superoxide dismutase in the mitochondrial intermembrane space. J Biol Chem 283:8446–8452

    Article  PubMed  CAS  Google Scholar 

  36. Witan H et al (2008) Heterodimer formation of wild-type and amyotrophic lateral sclerosis-causing mutant Cu/Zn-superoxide dismutase induces toxicity independent of protein aggregation. Hum Mol Genet 17:1373–1385

    Article  PubMed  CAS  Google Scholar 

  37. Prudencio M et al (2009) Modulation of mutant superoxide dismutase 1 aggregation by co-expression of wild-type. J Neurochem 103(4):1009–1018

    Google Scholar 

  38. Zhang F et al (2007) Interaction between familial amyotrophic lateral sclerosis (ALS)-linked SOD1 mutants and the dynein complex. J Biol Chem 282:16691–16699

    Article  PubMed  CAS  Google Scholar 

  39. Harraz MM et al (2008) SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J Clin Invest 118:659–670

    PubMed  CAS  Google Scholar 

  40. Graves M et al (2004) Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells. Amyotroph Lateral Scler Other Motor Neuron Disord 5:213–219

    Article  PubMed  CAS  Google Scholar 

  41. Boillée S et al (2006) ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52:39–59

    Article  PubMed  CAS  Google Scholar 

  42. Sasabe J et al (2007) D-serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis. EMBO J 26:4149–4159

    Article  PubMed  CAS  Google Scholar 

  43. Cudkowicz ME et al (2006) Trial of celecoxib in amyotrophic lateral sclerosis. Ann Neurol 60:22–31

    Article  PubMed  CAS  Google Scholar 

  44. Gordon PH et al (2007) Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 6:1045–1053

    Article  PubMed  CAS  Google Scholar 

  45. Miller R et al (2007) Phase II/III randomized trial of TCH346 in patients with ALS. Neurology 69:776–784

    Article  PubMed  CAS  Google Scholar 

  46. Shefner JM et al (2004) A clinical trial of creatine in ALS. Neurology 63:1656–1661

    PubMed  CAS  Google Scholar 

  47. Ilieva EV et al (2007) Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis. Brain 130:3111–3123

    Article  PubMed  Google Scholar 

  48. Kikuchi H 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

    Article  PubMed  CAS  Google Scholar 

  49. Gass JN et al (2002) Activation of an unfolded protein response during differentiation of antibody-secreting B cells. J Biol Chem 277:49047–49054

    Article  PubMed  CAS  Google Scholar 

  50. Lipson KL et al (2006) Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab 4:245–254

    Article  PubMed  CAS  Google Scholar 

  51. Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Diff 11:381–389

    Article  CAS  Google Scholar 

  52. Schubert U et al (2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404:770–774

    Article  PubMed  CAS  Google Scholar 

  53. Ellgaard L et al (1999) Setting the standards: quality control in the secretory pathway. Science 286:1882–1888

    Article  PubMed  CAS  Google Scholar 

  54. Isler JA et al (2005) Human cytomegalovirus infection activates and regulates the unfolded protein response. J Virol 79:6890–6899

    Article  PubMed  CAS  Google Scholar 

  55. Lee AS (1992) Mammalian stress response: induction of the glucose-regulated protein family. Curr Opin Cell Biol 4:267–273

    Article  PubMed  CAS  Google Scholar 

  56. Feldman DE et al (2005) The unfolded protein response: a novel component of the hypoxic stress response in tumors. Mol Cancer Res 3:597–605

    Article  PubMed  CAS  Google Scholar 

  57. Bartoszewski R et al (2008) Activation of the unfolded protein response by F508 CFTR. Am J Respir Cell Mol Biol 39:448–457

    Article  PubMed  CAS  Google Scholar 

  58. Ito D, Suzuki N (2009) Seipinopathy: a novel endoplasmic reticulum stress-associated disease. Brain 132(1):8–15

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  60. Nikawa J, Yamashita S (1992) IRE1 encodes a putative protein kinase containing a membrane-spanning domain and is required for inositol phototrophy in Saccharomyces cerevisiae. Mol Microbiol 6:1441–1446

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  62. Nikawa J et al (1996) Saccharomyces cerevisiae IRE2/HAC1 is involved in IRE1-mediated KAR2 expression. Nucleic Acids Res 24:4222–4226

    Article  PubMed  CAS  Google Scholar 

  63. Kohno K (2007) How transmembrane proteins sense endoplasmic reticulum stress. Antioxid Redox Signal 9:2295–2303

    Article  PubMed  CAS  Google Scholar 

  64. Bertolotti A et al (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2:326–332

    Article  PubMed  CAS  Google Scholar 

  65. Ye J et al (2000) ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 6:1355–1364

    Article  PubMed  CAS  Google Scholar 

  66. Harding HP et al (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397:271–274

    Article  PubMed  CAS  Google Scholar 

  67. Harding H et al (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108

    Article  PubMed  CAS  Google Scholar 

  68. Werner ED et al (1996) Proteasome-dependent endoplasmic reticulum-associated protein degradation: an unconventional route to a familiar fate. Proc Natl Acad Sci USA 93:13797–13801

    Article  PubMed  CAS  Google Scholar 

  69. Urano F et al (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664–666

    Article  PubMed  CAS  Google Scholar 

  70. Zinszner H et al (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12:982–995

    Article  PubMed  CAS  Google Scholar 

  71. Guegan C et al (2001) Recruitment of the mitochondrial-dependent apoptotic pathway in amyotrophic lateral sclerosis. J Neurosci 21:6569–6657

    PubMed  CAS  Google Scholar 

  72. Wong PC et al (1995) An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14:1105–1116

    Article  PubMed  CAS  Google Scholar 

  73. Mourelatos Z et al (1996) The Golgi apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the disease. Proc Natl Acad Sci USA 93:5472–5477

    Article  PubMed  CAS  Google Scholar 

  74. Stieber A et al (2000) Aggregation of ubiquitin and a mutant ALS-linked SOD1 protein correlate with disease progression and fragmentation of the Golgi apparatus. J Neurol Sci 173:53–62

    Article  PubMed  CAS  Google Scholar 

  75. Tiwari A et al (2005) Aberrantly increased hydrophobicity shared by mutants of Cu,Zn-superoxide dismutase in familial amyotrophic lateral sclerosis. J Biol Chem 280:29771–29779

    Article  PubMed  CAS  Google Scholar 

  76. Kanekura K et al (2004) Alsin, the product of ALS2 gene, suppresses SOD1 mutant neurotoxicity through RhoGEF domain by interacting with SOD1 mutants. J Biol Chem 279:19247–19256

    Article  PubMed  CAS  Google Scholar 

  77. Tobisawa S et al (2003) Mutant SOD1 linked to familial amyotrophic lateral sclerosis, but not wild-type SOD1, induces ER stress in COS7 cells and transgenic mice. Biochem Biophys Res Commun 303:496–503

    Article  PubMed  CAS  Google Scholar 

  78. Wootz H et al (2006) XIAP decreases caspase-12 cleavage and calpain activity in spinal cord of ALS transgenic mice. Exp Cell Res 312:1890–1898

    Article  PubMed  CAS  Google Scholar 

  79. Atkin JD et al (2006) Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. J Biol Chem 281:30152–30165

    Article  PubMed  CAS  Google Scholar 

  80. Nishitoh H et al (2008) ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. Genes Dev 22:1451–1464

    Article  PubMed  CAS  Google Scholar 

  81. Reimertz C et al (2003) Gene expression during ER stress-induced apoptosis in neurons: induction of the BH3-only protein Bbc3/PUMA and activation of the mitochondrial apoptosis pathway. J Cell Biol 162:587–597

    Article  PubMed  CAS  Google Scholar 

  82. Kieran D et al (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

    Article  PubMed  CAS  Google Scholar 

  83. Nishimura AL et al (2005) A common founder for amyotrophic lateral sclerosis type 8 (ALS8) in the Brazilian population. Hum Genet 118:499–500

    Article  PubMed  Google Scholar 

  84. Nishimura Y et al (1999) Molecular cloning and characterization of mammalian homologues of vesicle-associated membrane protein-associated (VAMP-associated) proteins. Biochem Biophys Res Commun 254:21–26

    Article  PubMed  CAS  Google Scholar 

  85. Skehel PA et al (1995) A VAMP-binding protein from Aplysia required for neurotransmitter release. Science 269:1580–1583

    Article  PubMed  CAS  Google Scholar 

  86. Kanekura K et al (2006) Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8). J Biol Chem 281:30223–30233

    Article  PubMed  CAS  Google Scholar 

  87. Teuling E et al (2007) Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates. J Neurosci 27:9801–9815

    Article  PubMed  CAS  Google Scholar 

  88. Kawano M et al (2006) Efficient trafficking of ceramide from the endoplasmic reticulum to the Golgi apparatus requires a VAMP-associated protein-interacting FFAT motif of CERT. J Biol Chem 281:30279–30288

    Article  PubMed  CAS  Google Scholar 

  89. Wyles JP et al (2002) Vesicle-associated membrane protein-associated protein-A (VAP-A) interacts with the oxysterol-binding protein to modify export from the endoplasmic reticulum. J Biol Chem 277:29908–29918

    Article  PubMed  CAS  Google Scholar 

  90. Amarilio R et al (2005) Differential regulation of endoplasmic reticulum structure through VAP-Nir protein interaction. J Biol Chem 280:5934–5944

    Article  PubMed  CAS  Google Scholar 

  91. Kagiwada S et al (1998) The Saccharomyces cerevisiae SCS2 gene product, a homolog of a synaptobrevin-associated protein, is an integral membrane protein of the endoplasmic reticulum and is required for inositol metabolism. J Bacteriol 180:1700–1708

    PubMed  CAS  Google Scholar 

  92. Nikawa J et al (1995) Cloning and sequence of the SCS2 gene, which can suppress the defect of INO1 expression in an inositol auxotrophic mutant of Saccharomyces cerevisiae. J Biochem 118:39–44

    PubMed  CAS  Google Scholar 

  93. Suzuki H et al (2009) ALS-linked P56S-VAPB, an aggregated loss-of-function mutant of VAPB, predisposes motor neurons to ER stress-induced death by inducing aggregation of co-expressed wild-type VAPB. J Neurochem 108(4):973–985

    Google Scholar 

  94. Gkogkas C et al (2008) VAPB interacts with and modulates the activity of ATF6. Hum Mol Genet 17:1517–1526

    Article  PubMed  CAS  Google Scholar 

  95. Cruz-Sánchez FF et al (1993) Amyotrophic lateral sclerosis brain banking: a proposal to standardize protocols and neuropathological diagnostic criteria. J Neural Transm Suppl 39:215–222

    PubMed  Google Scholar 

  96. Wakayama I (1992) Morphometry of spinal motor neurons in amyotrophic lateral sclerosis with special reference to chromatolysis and intracytoplasmic inclusion bodies. Brain Res 586:12–18

    Article  PubMed  CAS  Google Scholar 

  97. Oyanagi K (2008) Spinal anterior horn cells in sporadic amyotrophic lateral sclerosis show ribosomal detachment from, and cisternal distention of the rough endoplasmic reticulum. Neuropathol Appl Neurobiol 34(6):650–658

    Article  PubMed  CAS  Google Scholar 

  98. Atkin JD et al (2008) Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis. Neurobiol Dis 30:400–407

    Article  PubMed  CAS  Google Scholar 

  99. Wang JF et al (1999) Differential display PCR reveals novel targets for the mood-stabilizing drug valproate including the molecular chaperone GRP78. Mol Pharmacol 55:521–527

    PubMed  CAS  Google Scholar 

  100. Bown CD et al (2000) Increased expression of endoplasmic reticulum stress proteins following chronic valproate treatment of rat C6 glioma cells. Neuropharmacology 39:2162–2169

    Article  PubMed  CAS  Google Scholar 

  101. Kim AJ et al (2005) Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3. J Cell Sci 118:89–99

    Article  PubMed  CAS  Google Scholar 

  102. Shao L et al (2006) Mood stabilizing drug lithium increases expression of endoplasmic reticulum stress proteins in primary cultured rat cerebral cortical cells. Life Sci 78:1317–1323

    Article  PubMed  CAS  Google Scholar 

  103. Kakiuchi C et al (2003) Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nat Genet 35:171–175

    Article  PubMed  CAS  Google Scholar 

  104. Boyce M et al (2005) A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 307:935–939

    Article  PubMed  CAS  Google Scholar 

  105. Katayama T et al (1999) Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Nat Cell Biol 1:479–485

    Article  PubMed  CAS  Google Scholar 

  106. Smith WW et al (2005) Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity. Hum Mol Genet 14:3801–3811

    Article  PubMed  CAS  Google Scholar 

  107. Imai Y et al (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105:891–902

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are especially grateful to Dr. Ikuo Nishimoto. We thank Takako Hiraki and all members of the Departments of Anatomy and Cell Biology and Neuroscience for their cooperation. This work was indebted in part by grants to Masaaki Matsuoka (Kiban B and Houga) from the Japan Society for the Promotion of Science. We are also indebted to the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO).

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  1. Department of Cell Biology and Neuroscience, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Kohsuke Kanekura, Hiroaki Suzuki & Masaaki Matsuoka

  2. Department of Anatomy, School of Medicine, Keio University, Tokyo, Japan

    Kohsuke Kanekura, Hiroaki Suzuki & Sadakazu Aiso

  3. Japan Society for the Promotion of Science Research Fellow, Tokyo, Japan

    Hiroaki Suzuki

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  1. Kohsuke Kanekura
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Correspondence to Masaaki Matsuoka.

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Kanekura, K., Suzuki, H., Aiso, S. et al. ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis. Mol Neurobiol 39, 81–89 (2009). https://doi.org/10.1007/s12035-009-8054-3

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