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Endoplasmic Reticulum (ER) Stress in Amyotrophic Lateral Sclerosis (ALS)

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Endoplasmic Reticulum Stress in Health and Disease

Abstract

There have been considerable advances in understanding amyotrophic lateral sclerosis/motor neuron disease (ALS), particularly within the last 5 years with the identification of mutations in 4 key genes, TARDBP, FUS, VCP and VAPB that cause familial ALS. The strong association of TDP-43 with ubiquitinated protein aggregates in motor neurons, a hallmark of ALS in sporadic cases of ALS, clearly demonstrates the importance of these findings for understanding the pathology of sporadic cases. All of these genes are known to be involved in multiple cellular pathways but the key features that underpin ALS remain to be elucidated. What is known is that these causal genes result in a severe perturbation in the removal of mis-folded proteins with the accumulation of aggregated proteins. This may in part be due to protein degradation and mislocation and in some instances, it may be due to a direct effect on endogenous components of cellular protein control, the unfolded protein response (UPR) which operates within the endoplasmic reticulum (ER) and protein degradation pathways such as the ubiquitin proteasomal system (UPS) and early and late autophagy. Mutations in Vesicle associated protein-associated protein B (VAPB) and Valosin containing protein (VCP) cause familial Amyotrophic Lateral Sclerosis (FALS), which strongly indicates the importance of the prosurvival properties of these proteins in endoplasmic reticulum (ER) stress responses. The main components of ER stress and associated pathways include the unfolded protein response (UPR), ER–associated degradation (ERAD), the ubiquitin-proteasome system (UPS) and autophagy, all of which are known to be activated in ALS.

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Abbreviations

ER stress:

endoplasmic reticulum stress

VAPB:

vesicle associated protein-associated protein B

VCP:

valosin containing protein

ALS:

amyotrophic lateral sclerosis

MND:

motor neuron disease

UPR:

unfolded protein response

UPS:

ubiquitin proteasomal system

FALS:

familial amyotrophic lateral sclerosis

TDP-43:

TAR DNA-binding protein-43

TARDBP:

TAR DNA-binding protein gene

FUS:

fusion in sarcoma gene

FTD:

frontotemporal dementia

FTLD:

frontotemporal lobar degeneration

ERAD:

ER–associated degradation

References

  1. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672

    Article  PubMed  CAS  Google Scholar 

  2. Mackenzie IR (2007) The neuropathology and clinical phenotype of FTD with progranulin mutations. Acta Neuropathol 114:49–54

    Article  PubMed  Google Scholar 

  3. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, Mckenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208

    Article  PubMed  CAS  Google Scholar 

  4. Vance C, Rogelj B, Hortobagyi T, de Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211

    Article  PubMed  CAS  Google Scholar 

  5. Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, Kok F, Oliveira JR, Gillingwater T, Webb J, Skehel P, Zatz M (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 

  6. Johnson JO, Mandrioli J, Benatar M, Abramzon Y, van Deerlin VM, Trojanowski JQ, Gibbs JR, Brunetti M, Gronka S, Wuu J, Ding J, Mccluskey L, Martinez-Lage M, Falcone D, Hernandez DG, Arepalli S, Chong S, Schymick JC, Rothstein J, Landi F, Wang YD, Calvo A, Mora G, Sabatelli M, Monsurro MR, Battistini S, Salvi F, Spataro R, Sola P, Borghero G, Galassi G, Scholz SW, Taylor JP, Restagno G, Chio A, Traynor BJ (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68:857–864

    Article  PubMed  CAS  Google Scholar 

  7. Leigh PN, Anderton BH, Dodson A, Gallo JM, Swash M, Power DM (1988) Ubiquitin deposits in anterior horn cells in motor neurone disease. Neurosci Lett 93:197–203

    Article  PubMed  CAS  Google Scholar 

  8. Hirano A (1996) Neuropathology of ALS: an overview. Neurology 47:S63–66

    Article  PubMed  CAS  Google Scholar 

  9. 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

    Article  PubMed  Google Scholar 

  10. 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

    Article  PubMed  CAS  Google Scholar 

  11. Tobisawa S, Hozumi Y, Arawaka S, Koyama S, Wada M, Nagai M, Aoki M, Itoyama Y, Goto K, Kato T (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 

  12. Oh YK, Shin KS, Yuan J, Kang SJ (2008) Superoxide dismutase 1 mutants related to amyotrophic lateral sclerosis induce endoplasmic stress in neuro2a cells. J Neurochem 104:993–1005

    Article  PubMed  CAS  Google Scholar 

  13. Nishitoh H, Kadowaki H, Nagai A, Maruyama T, Yokota T, Fukutomi H, Noguchi T, Matsuzawa A, Takeda K, Ichijo H (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 

  14. Kikuchi H, Almer G, Yamashita S, Guegan C, Nagai M, Xu Z, Sosunov AA, Mckhann GM, 2nd, Przedborski S (2006) Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. Proc Natl Acad Sci U S A 103:6025–6030

    Article  PubMed  CAS  Google Scholar 

  15. Atkin JD, Farg MA, Turner BJ, Tomas D, Lysaght JA, Nunan J, Rembach A, Nagley P, Beart PM, Cheema SS, Horne MK (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 

  16. Wootz H, Hansson I, Korhonen L, Napankangas U, Lindholm D (2004) Caspase-12 cleavage and increased oxidative stress during motoneuron degeneration in transgenic mouse model of ALS. Biochem Biophys Res Commun 322:281–286

    Article  PubMed  CAS  Google Scholar 

  17. 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

    Article  PubMed  CAS  Google Scholar 

  18. Cheroni C, Marino M, Tortarolo M, Veglianese P, de Biasi S, Fontana E, Zuccarello LV, Maynard CJ, Dantuma NP, Bendotti C (2009) Functional alterations of the ubiquitin-proteasome system in motor neurons of a mouse model of familial amyotrophic lateral sclerosis. Hum Mol Genet 18:82–96

    Article  PubMed  CAS  Google Scholar 

  19. Urushitani M, Kurisu J, Tateno M, Hatakeyama S, Nakayama K, Kato S, Takahashi R (2004) CHIP promotes proteasomal degradation of familial ALS-linked mutant SOD1 by ubiquitinating Hsp/Hsc70. J Neurochem 90:231–244

    Article  PubMed  CAS  Google Scholar 

  20. Shinder GA, Lacourse MC, Minotti S, Durham HD (2001) Mutant Cu/Zn-superoxide dismutase proteins have altered solubility and interact with heat shock/stress proteins in models of amyotrophic lateral sclerosis. J Biol Chem 276:12791–12796

    Article  PubMed  CAS  Google Scholar 

  21. Tummala H, Jung C, Tiwari A, Higgins CM, Hayward LJ, Xu Z (2005) Inhibition of chaperone activity is a shared property of several Cu, Zn-superoxide dismutase mutants that cause amyotrophic lateral sclerosis. J Biol Chem 280:17725–17731

    Article  PubMed  CAS  Google Scholar 

  22. Takeuchi H, Kobayashi Y, Yoshihara T, Niwa J, Doyu M, Ohtsuka K, Sobue G (2002) Hsp70 and Hsp40 improve neurite outgrowth and suppress intracytoplasmic aggregate formation in cultured neuronal cells expressing mutant SOD1. Brain Res 949:11–22

    Article  PubMed  CAS  Google Scholar 

  23. Sharp PS, Akbar MT, Bouri S, Senda A, Joshi K, Chen HJ, Latchman DS, Wells DJ, de Belleroche J (2008) Protective effects of heat shock protein 27 in a model of ALS occur in the early stages of disease progression. Neurobiol Dis 30:42–55

    Article  PubMed  CAS  Google Scholar 

  24. 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

    Article  PubMed  CAS  Google Scholar 

  25. Nikawa J, Murakami A, Esumi E, Hosaka K (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 118:39–45

    PubMed  CAS  Google Scholar 

  26. Kagiwada S, Hosaka K, Murata M, Nikawa J, Takatsuki A (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 

  27. Nikawa J (1994) A cDNA encoding the human transforming growth factor beta receptor suppresses the growth defect of a yeast mutant. Gene 149:367–372

    Article  PubMed  CAS  Google Scholar 

  28. Soussan L, Burakov D, Daniels MP, Toister-Achituv M, Porat A, Yarden Y, Elazar Z (1999) ERG30, a VAP-33-related protein, functions in protein transport mediated by COPI vesicles. J Cell Biol 146:301–311

    Article  PubMed  CAS  Google Scholar 

  29. Prosser DC, Tran D, Gougeon PY, Verly C, Ngsee JK (2008) FFAT rescues VAPA-mediated inhibition of ER-to-Golgi transport and VAPB-mediated ER aggregation. J Cell Sci 121(Pt 18):3052–3061

    Article  PubMed  CAS  Google Scholar 

  30. Kawano M, Kumagai K, Nishijima M, Hanada K (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 

  31. Loewen CJ, Roy A, Levine TP (2003) A conserved ER targeting motif in three families of lipid binding proteins and in Opi1p binds VAP. EMBO J 22:2025–2035

    Article  PubMed  CAS  Google Scholar 

  32. Wyles JP, Mcmaster CR, Ridgway ND (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 

  33. Amarilio R, Ramachandran S, Sabanay H, Lev S (2005) Differential regulation of endoplasmic reticulum structure through VAP-Nir protein interaction. J Biol Chem 280:5934–5944

    Article  PubMed  CAS  Google Scholar 

  34. Kanekura K, Hashimoto Y, Kita Y, Sasabe J, Aiso S, Nishimoto I, Matsuoka M (2005) A Rac1/phosphatidylinositol 3-kinase/Akt3 anti-apoptotic pathway, triggered by AlsinLF, the product of the ALS2 gene, antagonizes Cu/Zn-superoxide dismutase (SOD1) mutant-induced motoneuronal cell death. J Biol Chem 280:4532–4543

    Article  PubMed  CAS  Google Scholar 

  35. Suzuki H, Kanekura K, Levine TP, Kohno K, Olkkonen VM, Aiso S, Matsuoka M (2009) ALS-linked P56S-VAPB, an aggregated loss-of-function mutant of VAPB, predisposes motor neurons to ER stress-related death by inducing aggregation of co-expressed wild-type VAPB. J Neurochem 108:973–985

    Article  PubMed  CAS  Google Scholar 

  36. Funke AD, Esser M, Kruttgen A, Weis J, Mitne-Neto M, Lazar M, Nishimura AL, Sperfeld AD, Trillenberg P, Senderek J, Krasnianski M, Zatz M, Zierz S, Deschauer M (2010) The p.P56S mutation in the VAPB gene is not due to a single founder: the first European case. Clin Genet 77:302–303

    Article  PubMed  CAS  Google Scholar 

  37. Millecamps S, Salachas F, Cazeneuve C, Gordon P, Bricka B, Camuzat A, Guillot-Noel L, Russaouen O, Bruneteau G, Pradat PF, Le Forestier N, Vandenberghe N, Danel-Brunaud V, Guy N, Thauvin-Robinet C, Lacomblez L, Couratier P, Hannequin D, Seilhean D, Le Ber I, Corcia P, Camu W, Brice A, Rouleau G, Leguern E, Meininger V (2010) SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations. J Med Genet 47:554–560

    Article  PubMed  CAS  Google Scholar 

  38. Marques VD, Barreira AA, Davis MB, Abou-Sleiman PM, Silva WA Jr, Zago MA, Sobreira C, Fazan V, Marques W Jr (2006) Expanding the phenotypes of the Pro56Ser VAPB mutation: proximal SMA with dysautonomia. Muscle Nerve 34:731–739

    Article  PubMed  CAS  Google Scholar 

  39. Chen HJ, Anagnostou G, Chai A, Withers J, Morris A, Adhikaree J, Pennetta G, de Belleroche JS (2010) Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis. J Biol Chem 285:40266–40281

    Article  PubMed  CAS  Google Scholar 

  40. Chai A, Withers J, Koh YH, Parry K, Bao H, Zhang B, Budnik V, Pennetta G (2008) hVAPB, the causative gene of a heterogeneous group of motor neuron diseases in humans, is functionally interchangeable with its Drosophila homologue DVAP-33A at the neuromuscular junction. Hum Mol Genet 17:266–280

    Article  PubMed  CAS  Google Scholar 

  41. Anagnostou G, Akbar MT, Paul P, Angelinetta C, Steiner TJ, de Belleroche J (2010) Vesicle associated membrane protein B (VAPB) is decreased in ALS spinal cord. Neurobiol Aging 31:969–985

    Article  PubMed  CAS  Google Scholar 

  42. Tudor EL, Galtrey CM, Perkinton MS, Lau KF, De Vos KJ, Mitchell JC, Ackerley S, Hortobagyi T, Vamos E, Leigh PN, Klasen C, Mcloughlin DM, Shaw CE, Miller CC (2010) Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology. Neuroscience 167(3):774–785

    Article  PubMed  CAS  Google Scholar 

  43. Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, Pestronk A, Whyte MP, Kimonis VE (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36:377–381

    Article  PubMed  CAS  Google Scholar 

  44. Halawani D, Latterich M (2006) p97: The cell’s molecular purgatory? Mol Cell 22:713–717

    Article  PubMed  CAS  Google Scholar 

  45. Wojcik C, Yano M, Demartino GN (2004) RNA interference of valosin-containing protein (VCP/p97) reveals multiple cellular roles linked to ubiquitin/proteasome-dependent proteolysis. J Cell Sci 117:281–292

    Article  PubMed  CAS  Google Scholar 

  46. Wojcik C, Rowicka M, Kudlicki A, Nowis D, Mcconnell E, Kujawa M, Demartino GN (2006) Valosin-containing protein (p97) is a regulator of endoplasmic reticulum stress and of the degradation of N-end rule and ubiquitin-fusion degradation pathway substrates in mammalian cells. Mol Biol Cell 17:4606–4618

    Article  PubMed  CAS  Google Scholar 

  47. Ju JS, Fuentealba RA, Miller SE, Jackson E, Piwnica-Worms D, Baloh RH, Weihl CC (2009) Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol 187:875–888

    Article  PubMed  CAS  Google Scholar 

  48. Tresse E, Salomons FA, Vesa J, Bott LC, Kimonis V, Yao TP, Dantuma NP, Taylor JP (2010) VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. Autophagy 6:217–227

    Article  PubMed  CAS  Google Scholar 

  49. Gitcho MA, Strider J, Carter D, Taylor-Reinwald L, Forman MS, Goate AM, Cairns NJ (2009) VCP mutations causing frontotemporal lobar degeneration disrupt localization of TDP-43 and induce cell death. J Biol Chem 284:12384–12398

    Article  PubMed  CAS  Google Scholar 

  50. Ritson GP, Custer SK, Freibaum BD, Guinto JB, Geffel D, Moore J, Tang W, Winton MJ, Neumann M, Trojanowski JQ, Lee VM, Forman MS, Taylor JP (2010) TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97. J Neurosci 30:7729–7739

    Article  PubMed  CAS  Google Scholar 

  51. Custer SK, Neumann M, Lu H, Wright AC, Taylor JP (2010) Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone. Hum Mol Genet 19:1741–1755

    Article  PubMed  CAS  Google Scholar 

  52. Koike M, Fukushi J, Ichinohe Y, Higashimae N, Fujishiro M, Sasaki C, Yamaguchi M, Uchihara T, Yagishita S, Ohizumi H, Hori S, Kakizuka A (2010) Valosin-containing protein (VCP) in novel feedback machinery between abnormal protein accumulation and transcriptional suppression. J Biol Chem 285:21736–21749

    Article  PubMed  CAS  Google Scholar 

  53. Mori-Konya C, Kato N, Maeda R, Yasuda K, Higashimae N, Noguchi M, Koike M, Kimura Y, Ohizumi H, Hori S, Kakizuka A (2009) p97/valosin-containing protein (VCP) is highly modulated by phosphorylation and acetylation. Genes Cells 14:483–497

    Article  PubMed  CAS  Google Scholar 

  54. Kim I, Shu CW, Xu W, Shiau CW, Grant D, Vasile S, Cosford ND, Reed JC (2009) Chemical biology investigation of cell death pathways activated by endoplasmic reticulum stress reveals cytoprotective modulators of ASK1. J Biol Chem 284:1593–1603

    Article  PubMed  CAS  Google Scholar 

  55. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’regan JP, Deng HX, et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62

    Article  PubMed  CAS  Google Scholar 

  56. Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, Miyamoto N, Showguchi-Miyata J, Okada Y, Singaraja R, Figlewicz DA, Kwiatkowski T, Hosler BA, Sagie T, Skaug J, Nasir J, Brown RH Jr, Scherer SW, Rouleau GA, Hayden MR, Ikeda JE (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 

  57. Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, Cole N, Gascon G, Yagmour A, Ben-Hamida M, Pericak-Vance M, Hentati F, Siddique T (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 

  58. Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA, Nicholson GA, Auer-Grumbach M, Wagner K, De Jonghe P, Griffin JW, Fischbeck KH, Timmerman V, Cornblath DR, Chance PF (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 

  59. Puls I, Jonnakuty C, Lamonte BH, Holzbaur EL, Tokito M, Mann E, Floeter MK, Bidus K, Drayna D, Oh SJ, Brown RH, Jr, Ludlow CL, Fischbeck KH (2003) Mutant dynactin in motor neuron disease. Nat Genet 33:455–456

    Article  PubMed  CAS  Google Scholar 

  60. Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C, Patterson V, Swingler R, Kieran D, Prehn J, Morrison KE, Green A, Acharya KR, Brown RH, Jr, Hardiman O (2006) ANG mutations segregate with familial and ‘sporadic’ amyotrophic lateral sclerosis. Nat Genet 38:411–413

    Article  PubMed  CAS  Google Scholar 

  61. Mitchell J, Paul P, Chen HJ, Morris A, Payling M, Falchi M, Habgood J, Panoutsou S, Winkler S, Tisato V, Hajitou A, Smith B, Vance C, Shaw C, Mazarakis ND, de Belleroche J (2010) Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase. Proc Natl Acad Sci U S A 107:7556–7561

    Article  PubMed  CAS  Google Scholar 

  62. Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465:223–226

    Article  PubMed  CAS  Google Scholar 

  63. Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, Jiang H, Hirano M, Rampersaud E, Jansen GH, Donkervoort S, Bigio EH, Brooks BR, Ajroud K, Sufit RL, Haines JL, Mugnaini E, Pericak-Vance MA, Siddique T (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477:211–215

    Article  PubMed  CAS  Google Scholar 

  64. 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

    Article  PubMed  CAS  Google Scholar 

  65. 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

    Article  PubMed  CAS  Google Scholar 

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  1. Neurogenetics Group, Centre for Neuroscience, Department of Medicine, Imperial College London, Room 407 Burlington Danes Building, Hammersmith Hospital campus, Du Cane Road, W12 0NN, London, UK

    Dr. Han-Jou Chen & Prof. Jackie de Belleroche

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Correspondence to Han-Jou Chen .

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  1. Dept Molec Cell Bio, K.U. Leuven, Harestraat/Gasthuisberg, B-3000 Leuven, 3000, Belgium

    Patrizia Agostinis

  2. School of Natural Science, Department of Biochemistry, NUI Galway, University Road, Galway, Ireland

    Samali Afshin

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Chen, HJ., de Belleroche, J. (2012). Endoplasmic Reticulum (ER) Stress in Amyotrophic Lateral Sclerosis (ALS). In: Agostinis, P., Afshin, S. (eds) Endoplasmic Reticulum Stress in Health and Disease. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4351-9_14

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