Skip to main content
SpringerLink
Log in

Expression of an endoplasmic reticulum-resident chaperone, glucose-regulated stress protein 78, in the spinal cord of a mouse model of amyotrophic lateral sclerosis

  • Regular Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

The immunohistochemical localization of glucose-regulated protein 78/BiP (GRP78), a chaperone protein that primarily resides within the lumen of the endoplasmic reticulum, was investigated in the lumbar spinal cord of mutant copper/zinc superoxide dismutase (SOD1) transgenic mice. Re-staining techniques were used to determine the immunoreactivity with anti-GRP78 antibody of abnormal structures observed by hematoxylin and eosin staining. Besides its physiological localization in the neuronal and glial cytoplasm, GRP78 was expressed in Lewy body-like hyaline inclusions, in irregularly-shaped eosinophilic structures without an apparent halo, and in cord-like swollen neurites. These different sites were invariably also immunopositive for ubiquitin, suggesting them to be pathological structures. The topographic distribution of GRP78 expression closely resembled that of SOD1. Moreover, our chronological quantitative analysis demonstrated that virtually all the Lewy body-like hyaline inclusions were immunolabeled by the anti-GRP78 antibody, irrespective to the age of mice examined, even at the presymptomatic stages. These findings imply that GRP78 may bind to, or at least be closely associated with, SOD1, and may participate in the pathological processes leading to inclusion formation. Thus, the results suggest that dysfunction of GRP78 and subsequent derangement of the system responding to unfolded proteins may be involved in the pathogenesis of familial amyotrophic lateral sclerosis caused by a mutation of the human SOD1 gene.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Beckman JS, Carson M, Smith CD, Koppenol WH (1993) ALS, SOD and peroxynitrite. Nature 364:584

    Article  PubMed  Google Scholar 

  2. Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292:1552–1555

    Article  PubMed  Google Scholar 

  3. Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, Sisodia SS, Rothstein JD, Borchelt DR, Price DL, Cleveland DW (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  Google Scholar 

  4. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2:326–332

    Article  PubMed  Google Scholar 

  5. Carri MT, Battistoni A, Polizio F, Desideri A, Rotilio G (1994) Impaired copper binding by the H46R mutant of human Cu,Zn superoxide dismutase, involved in amyotrophic lateral sclerosis. FEBS Lett 356:314–316

    Article  PubMed  Google Scholar 

  6. Dal Canto MC, Gurney ME (1995) Neuropathological changes in two lines of mice carrying a transgene for mutant human Cu,ZN SOD, and in mice overexpressing wild type human SOD: a model of familial amyotrophic lateral sclerosis (FALS). Brain Res 676:25–40

    Article  PubMed  Google Scholar 

  7. Durham HD, Roy J, Dong L, Figlewicz DA (1997) Aggregation of mutant Cu/Zn superoxide dismutase proteins in a culture model of ALS. J Neuropathol Exp Neurol 56:523–530

    PubMed  Google Scholar 

  8. Fribley A, Zeng Q, Wang CY (2004) Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells. Mol Cell Biol. 24:9695–9704

    Google Scholar 

  9. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, et al (1994) Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264:1772–1775

    PubMed  Google Scholar 

  10. Hayashi T, Saito A, Okuno S, Ferrand-Drake M, Chan PH (2003) Induction of GRP78 by ischemic preconditioning reduces endoplasmic reticulum stress and prevents delayed neuronal cell death. J Cereb Blood Flow Metab. 23:949–961

    Google Scholar 

  11. Hirano A, Nakano I, Kurland LT, Mulder DW, Holley PW, Saccomanno G (1984) Fine structural study of neurofibrillary changes in a family with amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 43:471–480

    PubMed  Google Scholar 

  12. Hirano K, Fukuta M, Adachi T, Hayashi K, Sugiura M, Mori Y, Toyoshi K (1985) In vitro synthesis of superoxide dismutases of rat liver. Biochem Biophys Res Commun 129:89–94

    Article  PubMed  Google Scholar 

  13. Ikezoe K, Furuya H, Ohyagi Y, Osoegawa M, Nishino I, Nonaka I, Kira J (2003) Dysferlin expression in tubular aggregates: their possible relationship to endoplasmic reticulum stress. Acta Neuropathol 105:603–609

    PubMed  Google Scholar 

  14. Kaufman RJ (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13:1211–1233

    PubMed  Google Scholar 

  15. Koide T, Igarashi S, Kikugawa K, Nakano R, Inuzuka T, Yamada M, Takahashi H, Tsuji S (1998) Formation of granular cytoplasmic aggregates in COS7 cells expressing mutant Cu/Zn superoxide dismutase associated with familial amyotrophic lateral sclerosis. Neurosci Lett 257:29–32

    Article  PubMed  Google Scholar 

  16. Kunst CB, Mezey E, Brownstein MJ, Patterson D (1997) Mutations in SOD1 associated with amyotrophic lateral sclerosis cause novel protein interactions. Nat Genet 15:91–94

    Article  PubMed  Google Scholar 

  17. Lee AS (2001) The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem Sci 26:504–510

    Article  PubMed  Google Scholar 

  18. Nishida CR, Gralla EB, Valentine JS (1994) Characterization of three yeast copper-zinc superoxide dismutase mutants analogous to those coded for in familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 91:9906–9910

    PubMed  Google Scholar 

  19. Qian Y, Tiffany-Castiglioni E (2003) Lead-induced endoplasmic reticulum (ER) stress responses in the nervous system. Neurochem Res 28:153–162

    Article  PubMed  Google Scholar 

  20. Raben N, Danon M, Lu N, Lee E, Shliselfeld L, Skurat AV, Roach PJ, Lawrence JC Jr, Musumeci O, Shanske S, et al (2001) Surprises of genetic engineering: a possible model of polyglucosan body disease. Neurology 56:1739–1745

    PubMed  Google Scholar 

  21. Rao RV, Peel A, Logvinova A, Rio G del, Hermel E, Yokota T, Goldsmith PC, Ellerby LM, Ellerby HM, Bredesen DE. (2002) Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78. FEBS Lett 514:122–128

    PubMed  Google Scholar 

  22. 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  Google Scholar 

  23. Saito T, Shinzawa H, Togashi H, Wakabayashi H, Ukai K, Takahashi T, Ishikawa M, Dobashi M, Imai Y (1989) Ultrastructural localization of Cu, Zn-SOD in hepatocytes of patients with various liver diseases. Histol Histopathol 4:1–6

    PubMed  Google Scholar 

  24. 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. Dev Cell 3:99–111

    Article  PubMed  Google Scholar 

  25. Shibata N, Hirano A, Kobayashi M, Siddique T, Deng HX, Hung WY, Kato T, Asayama K (1996) Intense superoxide dismutase-1 immunoreactivity in intracytoplasmic hyaline inclusions of familial amyotrophic lateral sclerosis with posterior column involvement. J Neuropathol Exp Neurol 55:481–490

    PubMed  Google Scholar 

  26. Shibata N, Hirano A, Kobayashi M, Dal Canto MC, Gurney ME, Komori T, Umahara T, Asayama K (1998) Presence of Cu/Zn superoxide dismutase(SOD) immunoreactivity in neuronal hyaline inclusions in spinal cords from mice carrying a transgene for Gly93Ala mutant human Cu/Zn SOD. Acta Neuropathol 95:136–142

    Article  PubMed  Google Scholar 

  27. 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  Google Scholar 

  28. Trieu VN, Uckun FM (1999) Genistein is neuroprotective in murine models of familial amyotrophic lateral sclerosis and stroke. Biochem Biophys Res Commun 258:685–688

    Article  PubMed  Google Scholar 

  29. Veldink JH, Bar PR, Joosten EA, Otten M, Wokke JH, Berg LH van den (2003) Sexual differences in onset of disease and response to exercise in a transgenic model of ALS. Neuromuscul Disord 13:737–43

    Article  PubMed  Google Scholar 

  30. Wiedau-Pazos M, Goto JJ, Rabizadeh S, Gralla EB, Roe JA, Lee MK, Valentine JS, Bredesen DE (1996) Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis. Science 271:515–518

    PubMed  Google Scholar 

  31. Zhang B, Tu P, Abtahian F, Trojanowski JQ, Lee VM (1997) Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation. J Cell Biol 139:1307–1315

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors express their sincere appreciation to Prof. Ryosuke Takahashi (Department of Neurology, Faculty of Medicine, Kyoto University) and to Prof. Toshio Kawamata (Faculty of Health Sciences, Kobe University School of Medicine) for their helpful suggestions. This study was supported in part by a Grant-in-Aid for Scientific research from the Japan Society for the Promotion of Science. (No. 15590917).

Author information

Authors and Affiliations

  1. Department of Neurology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi-shi, 570-8507, Osaka, Japan

    Reika Wate, Hidefumi Ito, Jian Hua Zhang, Shizuo Ohnishi, Satoshi Nakano & Hirofumi Kusaka

Authors
  1. Reika Wate
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hidefumi Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jian Hua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shizuo Ohnishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Satoshi Nakano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hirofumi Kusaka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hidefumi Ito.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wate, R., Ito, H., Zhang, J.H. et al. Expression of an endoplasmic reticulum-resident chaperone, glucose-regulated stress protein 78, in the spinal cord of a mouse model of amyotrophic lateral sclerosis. Acta Neuropathol 110, 557–562 (2005). https://doi.org/10.1007/s00401-005-1080-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-005-1080-y

Keywords

Search

Navigation