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Promoter polymorphisms modulating HSPA5 expression may increase susceptibility to Taiwanese Alzheimer’s disease

  • Alzheimer's Disease and Related Disorders - Original Article
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Abstract

Endoplasmic reticulum (ER) chaperone heat shock 70 kDa protein 5 (HSPA5/GRP78) is known to be involved in the metabolism of amyloid precursor protein and neuronal death in Alzheimer’s disease (AD) could arise from dysfunction of the ER. Through a case–control study and an expression assay, we investigated the association of HSPA5 −415 G/A (rs391957), −370 C/T (rs17840761) and −180 del/G (rs3216733) polymorphisms with Taiwanese AD. The overall genotype and allele frequency distribution at the completely linked −415 G/A and −180 del/G sites showed significant difference between AD cases and controls (P = 0.020 and 0.009, respectively). A decrease in risk of developing AD was demonstrated for −415 AA/−180 GG genotype [OR = 0.38, 95% confidence interval (CI) = 0.18–0.75, P = 0.007] and −415 A/−180 G allele (OR = 0.69, 95% CI = 0.51–0.91, P = 0.009). The HSPA5 transcriptional activity of the −415 A/−180 G allele was significantly lower than that of the −415 G/−180 del alleles, whereas induction of HSPA5 expression after ER stress was markedly increased in the cells with the −415 A/−180 G allele. Therefore, our preliminary results may suggest a protective role of the HSPA5 −415 A/−180 G allele in Taiwanese AD susceptibility.

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References

  • Abecasis GR, Cookson WO (2000) GOLD-graphical overview of linkage disequilibrium. Bioinformatics 16:182–183

    Article  PubMed  CAS  Google Scholar 

  • Cheverud JM (2001) A simple correction for multiple comparisons in interval mapping genome scans. Heredity 87:52–58

    Article  PubMed  CAS  Google Scholar 

  • Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923

    Article  PubMed  CAS  Google Scholar 

  • Hardy J (1997) Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci 20:154–159

    Article  PubMed  CAS  Google Scholar 

  • Hoozemans JJ, Veerhuis R, Van Haastert ES, Rozemuller JM, Baas F, Eikelenboom P, Scheper W (2005) The unfolded protein response is activated in Alzheimer’s disease. Acta Neuropathol 110:165–172

    Article  PubMed  CAS  Google Scholar 

  • Hoshino T, Nakaya T, Araki W, Suzuki K, Suzuki T, Mizushima T (2007) Endoplasmic reticulum chaperones inhibit the production of amyloid-beta peptides. Biochem J 402:581–589

    Article  PubMed  CAS  Google Scholar 

  • Kakimura J, Kitamura Y, Takata K, Tsuchiya D, Taniguchi T, Gebicke-Haerter PJ, Smith MA, Perry G, Shimohama S (2002) Possible involvement of ER chaperone Grp78 on reduced formation of amyloid-beta deposits. Ann N Y Acad Sci 977:327–332

    PubMed  CAS  Google Scholar 

  • Kakiuchi C, Ishiwata M, Nanko S, Kunugi H, Minabe Y, Nakamura K, Mori N, Fujii K, Umekage T, Tochigi M, Kohda K, Sasaki T, Yamada K, Yoshikawa T, Kato T (2005) Functional polymorphisms of HSPA5: possible association with bipolar disorder. Biochem Biophys Res Commun 336:1136–1143

    Article  PubMed  CAS  Google Scholar 

  • Katayama T, Imaizumi K, Honda A, Yoneda T, Kudo T, Takeda M, Mori K, Rozmahel R, Fraser P, George-Hyslop PS, Tohyama M (2001) Disturbed activation of endoplasmic reticulum stress transducers by familial Alzheimer’s disease-linked presenilin-1 mutation. J Biol Chem 276:43446–43454

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Lee AS (2005) The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods 35:373–381

    Article  PubMed  CAS  Google Scholar 

  • Li WW, Hsiung Y, Zhou Y, Roy B, Lee AS (1997) Induction of the mammalian GRP78/BiP gene by Ca2+ depletion and formation of aberrant proteins: activation of the conserved stress-inducible grp core promoter element by the human nuclear factor YY1. Mol Cell Biol 17:54–60

    PubMed  Google Scholar 

  • Marcus N, Green M (1997) NF-Y, a CCAAT box-binding protein, is one of the trans-acting factors necessary for the response of the murine ERp72 gene to protein traffic. DNA Cell Biol 16:1123–1131

    Article  PubMed  CAS  Google Scholar 

  • McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under auspices of department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:934–944

    Google Scholar 

  • Moroney JT, Bagiella E, Desmond DW, Hachinski VC, Mölsä PK, Gustafson L, Brun A, Fischer P, Erkinjuntti T, Rosen W, Paik MC, Tatemichi TK (1997) Meta-analysis of the Hachinski Ischemic Score in pathologically verified Dementias. Neurology 49:1096–1105

    PubMed  CAS  Google Scholar 

  • Nyholt DR (2004) A simple correction for multiple testing for singlenucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74:765–769

    Article  PubMed  CAS  Google Scholar 

  • Parker R, Phan T, Baumeister P, Roy B, Cheriyath V, Roy AL, Lee AS (2001) Identification of TFII-I as the endoplasmic reticulum stress response element binding factor ERSF: its autoregulation by stress and interaction with ATF6. Mol Cell Biol 21:3220–3233

    Article  PubMed  CAS  Google Scholar 

  • Sato N, Imaizumi K, Manabe T, Taniguchi M, Hitomi J, Katayama T, Yoneda T, Morihara T, Yasuda Y, Takagi T, Kudo T, Tsuda T, Itoyama Y, Makifuchi T, Fraser PE, St George-Hyslop P, Tohyama M (2001) Increased production of beta-amyloid and vulnerability to endoplasmic reticulum stress by an aberrant spliced form of presenilin 2. J Biol Chem 276:2108–2114

    Article  PubMed  CAS  Google Scholar 

  • Schröder M, Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569:29–63

    PubMed  Google Scholar 

  • Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989

    Article  PubMed  CAS  Google Scholar 

  • Wang HK, Fung HC, Hsu WC, Wu YR, Lin JC, Ro LS, Chang KH, Hwu FJ, Hsu Y, Huang SY, Lee-Chen GJ, Chen CM (2006) Apolipoprotein E, angiotensin-converting enzyme and kallikrein gene polymorphisms and the risk of Alzheimer’s disease and vascular dementia. J Neural Transm 113:1499–1509

    Article  PubMed  CAS  Google Scholar 

  • Yang Y, Turner RS, Gaut JR (1998) The chaperone BiP/GRP78 binds to amyloid precursor protein and decreases Abeta40 and Abeta42 secretion. J Biol Chem 273:25552–25555

    Article  PubMed  CAS  Google Scholar 

  • 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 273:33741–33749

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to thank all the patients and normal controls who took part in the study. Portions of this work were supported by grants NSC-95-2311-B-003-004-MY2 from the National Science Council, Executive Yuan, 96TOP001 from National Taiwan Normal University and CMRPG 33108 from Chang Gung Memorial Hospital.

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Authors and Affiliations

  1. Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, 10507, Taiwan

    W.-C. Hsu, H.-C. Fung, J.-C. Lin, H.-P. Hsu, Y.-R. Wu, L.-S. Ro & C.-M. Chen

  2. Department of Life Science, National Taiwan Normal University, Taipei, 11677, Taiwan

    H.-K. Wang, L.-C. Lee, F.-J. Hu, Y.-T. Chang & G.-J. Lee-Chen

  3. Department of Neurology, St Paul Hospital, Taoyuan, Taiwan

    J.-C. Lin & H.-P. Hsu

Authors
  1. W.-C. Hsu
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  2. H.-K. Wang
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  3. L.-C. Lee
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  4. H.-C. Fung
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  5. J.-C. Lin
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  6. H.-P. Hsu
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  7. Y.-R. Wu
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  8. L.-S. Ro
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  9. F.-J. Hu
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  10. Y.-T. Chang
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  11. G.-J. Lee-Chen
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  12. C.-M. Chen
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Corresponding authors

Correspondence to G.-J. Lee-Chen or C.-M. Chen.

Additional information

W.-C. Hsu and H.-K. Wang have equally contributed to the paper.

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Hsu, WC., Wang, HK., Lee, LC. et al. Promoter polymorphisms modulating HSPA5 expression may increase susceptibility to Taiwanese Alzheimer’s disease. J Neural Transm 115, 1537–1543 (2008). https://doi.org/10.1007/s00702-008-0117-5

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  • DOI: https://doi.org/10.1007/s00702-008-0117-5

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