Skip to main content

Advertisement

SpringerLink
Log in

Potential Interaction Between the GARS-AIRS-GART Gene and CP2/LBP-1c/LSF Transcription Factor in Down Syndrome-related Alzheimer Disease

  • Original Paper
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

(1) GARS-AIRS-GART is an important candidate gene in studies of Down syndrome (DS)-related Alzheimer’s disease (AD), due to its chromosomal localization (21q22.1) in the Down syndrome critical region, involvement in de novo purine biosynthesis, and over-expression in DS brain. The aim of this study was to identify factor(s) likely to enhance transcription of GARS-AIRS-GART in DS-related AD. (2) Based on a bio-informatics approach, the PromoterInspector, Promoter Scan II, and EBI toolbox CpG plot software programs were used to identify GARS-AIRS-GART sequences important for gene transcription. Transcription factor binding motifs within these regions were mapped with the help of the MatInspector and TFSEARCH programs. Factors implicated in neurodevelopment or neurodegeneration were the focus of attention, and mining of human (T1Dbase) and murine (GNF) expression databases revealed information on the regional distribution of these factors and their relative abundance vis-a-vis GARS-AIRS-GART. (3) The Leader-binding protein 1-c (LBP-1c/CP2/LSF) emerged as a promising candidate from these studies, as MatInspector and TFSEARCH analyses revealed a total of four CP2 binding sites with potential for functional interaction(s) within the promoter and CpG islands of GARS-AIRS-GART. Furthermore, two of these sites harbor sequences for methylation-sensitive restriction enzymes, which suggest that methylation status may, in part, regulate CP2-mediated transcription of GARS-AIRS-GART. A search of T1Dbase and GNF expression databases reveals co-expression of CP2 and GARS-AIRS-GART in brain regions relevant to DS-related AD. (4) The virtual screen identified CP2/LBP-1c/LSF as a factor that likely mediates enhanced transcription of GARS-AIRS-GART in DS-related AD.

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Aimi J, Qiu H, Williams J, Zalkin W, Dixon JE (1990) De novo purine biosynthesis: cloning of human and avian cDNAs encoding the tri-functional glycinamide ribonucleotide synthetase-aminoimidazole ribonucleotide synthetase-glycinamide ribonucleotide transformylase by functional complementation in E. coli. Nucl Acids Res 18:6665–6672

    Article  PubMed  CAS  Google Scholar 

  • Akiyama, Y (1998) “TFSEARCH: Searching Transcription Factor Binding Sites”. http://www.rwcp.or.jp/papia/

  • Allore R, O’Hanlon D, Price R, Neilson K, Willfard HF, Cox DR, Marks A, Dunn RJ (1988) Gene encoding the β subunit of S100 protein is on chromosome 21: implications for Down syndrome. Science 239:1311–1313

    Article  PubMed  CAS  Google Scholar 

  • Allore R, Friend WC, O’Hanlon D, Neilson KM, Buamal R, Dunn RJ, Marks A (1990) Cloning and expression of human S100β gene. J Biol Chem 265:15537–15543

    PubMed  CAS  Google Scholar 

  • Appleton MD, Haab W, Burti U, Orsulak PJ (1969) Plasma urate levels in mongolism. Am J Ment Defic 74:196–199

    PubMed  CAS  Google Scholar 

  • Brodsky G, Barnes T, Bleskan J, Becker L, Cox M, Patterson D (1997) The human GARS-AIRS-GART gene encodes two proteins which are differentially expressed during human brain development and temporally over-expressed in cerebellum of individuals with Down syndrome. Hum Mol Genet 6:2043–2050

    Article  PubMed  CAS  Google Scholar 

  • Brooksbank BW, Balazs R (1984) Superoxide dismutase, glutathione peroxidase and lipoperoxidation in Down’s syndrome fetal brain. Brain Res 318:37–44

    PubMed  CAS  Google Scholar 

  • Cunningham JM, Vanin EF, Tran N, Valentine M, Jane SM (1995) The human transcription factor CP2 (TFCP2), a component of the human gamma-globin stage selector protein, maps to chromosome region 12q13 and is within 250 kb of the NF-E2 gene. Genomics 30:398–399

    PubMed  CAS  Google Scholar 

  • Degrell I, Niklasson F (1988) Purine metabolites in the CSF in presenile and senile dementia of Alzheimer type, and in multi infarct dementia. Arch Gerontol Geriatr 7:173–178

    Article  PubMed  CAS  Google Scholar 

  • Dynlacht BD, Attardi LD, Admon A, Freeman M, Tjian R (1989) Functional analysis of NTF-1, a developmentally regulated Drosophila transcription factor that binds neuronal cis elements. Genes Dev 3:1677–1688

    Article  PubMed  CAS  Google Scholar 

  • Epstein CJ (2001) Down syndrome (Trisomy21). In: Scriver CR, Beaudet AL, Valle D, Sly WS, Childs B, Kinzler KW, Vogelstein B (eds) The metabolic and molecular basis of inherited disease, vol I. McGraw-Hill Medical Publishing Division, pp 1223–1256

  • Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–706

    Article  PubMed  CAS  Google Scholar 

  • Hard RG, Benkovic SJ, Van Keuren ML, Graw SL, Drabkin HA, Patterson D (1986) Assignment of a third purine biosynthetic gene (glycinamide ribonucleotide transformylase) to human chromosome 21. Am J Hum Genet 39:179–185

    Google Scholar 

  • Head E, Lott IT (2004) Down syndrome and beta-amyloid deposition. Curr Opin Neurol 17:95–100

    Article  PubMed  CAS  Google Scholar 

  • Huminiecki L, Lloyd AT, Wolfe KH (2003) Congruence of tissue expression profiles from Gene Expression Atlas, SAGEmap and TissueInfo databases. BMC Genomics 4(1):31

    Article  PubMed  Google Scholar 

  • Kim H-S, Kim E-M, Lee J-P, Park CH, Kim S, Seo J-H, Chang K-A, Yu E, Jeong S-J, Chong YH, Suh Y-H (2003) C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase-3β expression. FASEB J 17:1951–1953

    PubMed  CAS  Google Scholar 

  • Lim LC, Swendeman SL, Shefferey M (1992) Molecular cloning of α-Globin transcription factor CP2. Mol Cell Biol 12:828–835

    PubMed  CAS  Google Scholar 

  • Lim LC, Fang L, Swendeman SL, Shefferey M (1993) Characterization of the molecularly cloned murine alpha-globin transcription factor CP2. J Biol Chem 268:18008–18017

    PubMed  CAS  Google Scholar 

  • Murata T, Nitta M, Yasuda K (1998) Transcription factor CP2 is essential for lens-specific expression of the chicken αA-crystallin gene. Genes Cells 3:443–457

    Article  PubMed  CAS  Google Scholar 

  • Panza F, D'Introno A, Colaciccco AM, Capurso C, Basile AM, Torres F, Capurso A, Solfrizzi V (2004) LBP-1c/CP2/LSF gene polymorphism and risk of sporadic Alzheimer’s disease. J Neurol Neurosurg Psychiatry 75:166–168

    PubMed  CAS  Google Scholar 

  • Patterson D, Graw S, Jones C (1981) Demonstration by somatic cell genetics, of coordination of genes for two enzymes of purine synthesis assigned to human chromosome 21. Proc Natl Acad Sci USA 78:405–409

    Article  PubMed  CAS  Google Scholar 

  • Prestridge DS (1995) Predicting Pol II Promoter Sequences Using Transcription Factor Binding Sites. J Mol Biol 249:923–932

    Article  PubMed  CAS  Google Scholar 

  • Puukka R, Puukka M, Perkkila L, Kouvalainen K (1986) Levels of some purine metabolizing enzymes in lymphocytes from patients with Down syndrome. Biochem Med Metab Biol 36:45–50

    Article  PubMed  CAS  Google Scholar 

  • Quandt K, Frech K, Karas H, Wingender E, Werner T (1995) MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data. Nucl Acids Res 23:4878–4884

    Article  PubMed  CAS  Google Scholar 

  • Rathbone MP, Middlemiss PJ, Gysbers JW, Andrew C, Herman MAR, Reed JK, Ciccarelli R, Di Iorio P, Caciagli F (1999) Trophic effects of purines in neurons and glial cells. Prog Neurobiol 59:663–690

    Article  PubMed  CAS  Google Scholar 

  • Rice P, Longden I, Bleasby A (2000) EMBOSS: the European Molecular Biology Open Software Suite. Trends Genet 16:276–277

    Article  PubMed  CAS  Google Scholar 

  • Scherf M, Klingenhoff A, Werner T (2000) Highly specific localization of promoter regions in large genomic sequences by PromoterInspector: A novel context analysis approach. J Mol Biol 297:599–606

    Article  PubMed  CAS  Google Scholar 

  • Schupf N, Kapell D, Le JH, Ottman R, Mayeux R (1994) Increased risk of Alzheimer’s disease in mothers of adults with Down’s syndrome. Lancet 344:353–356

    Article  PubMed  CAS  Google Scholar 

  • Schupf N, Kapell D, Nightingale B, Le JH, Mohlenhoff J, Bewley S, Ottman R, Mayeux R (2001) Specificity of the five-fold increase in AD in mothers of adults with Down syndrome. Neurology 57:979–984

    PubMed  CAS  Google Scholar 

  • Shirra MK, Hansen U (1998) LSF and NTF-1 share a conserved DNA recognition motif yet require different oligomerization states to form a stable protein-DNA complex. J Biol Chem 273:19260–19268

    Article  PubMed  CAS  Google Scholar 

  • Skrabanek L, Campagne F (2001) TissueInfo: high-throughput identification of tissue expression profiles and specificity. Nucl Acids Res 29(21):e102

    Article  PubMed  CAS  Google Scholar 

  • St George-Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC, Myers RH, Feldman RG, Pollen D, Drachman D (1987) The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science 235:885–890

    Article  PubMed  CAS  Google Scholar 

  • Su AI, Cooke MP, Ching KA, Hakok Y, Walker JR, Wiltshire T, Orth AP, Vega RG, Sapinoso LM, Moqrich A, Patapoutian A, Hampton GM, Schultz PG, Hogenesch JB (2002) Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci USA 99:4465–4470

    Article  PubMed  CAS  Google Scholar 

  • Swendeman SL, Spielholz C, Jenkins NA, Gilbert DJ, Copeland NG, Sheffery M (1994) Characterization of the genomic structure, chromosomal location, promoter, and developmental expression of the alpha-globin transcription factor CP2. J Biol Chem 269:11663–11671

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Disha Banerjee is the recipient of a Senior Research Fellowship from CSIR grant 27(0131)/04/EMR-II awarded to Krishnadas Nandagopal. We thank the anonymous referee for helpful comments on our manuscript.

Author information

Authors and Affiliations

  1. Manovikas Biomedical Research and Diagnostic Centre, Manovikas Kendra Rehabilitation and Research Institute for the Handicapped, 482 Madudah, Plot I-24, Sector-J, Eastern Metropolitan Bypass, Kolkata, 700107, India

    Disha Banerjee & Krishnadas Nandagopal

Authors
  1. Disha Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Krishnadas Nandagopal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Krishnadas Nandagopal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Banerjee, D., Nandagopal, K. Potential Interaction Between the GARS-AIRS-GART Gene and CP2/LBP-1c/LSF Transcription Factor in Down Syndrome-related Alzheimer Disease. Cell Mol Neurobiol 27, 1117–1126 (2007). https://doi.org/10.1007/s10571-007-9217-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-007-9217-2

Keywords

Search

Navigation