Potential Interaction Between the GARS-AIRS-GART Gene and CP2/LBP-1c/LSF Transcription Factor in Down Syndrome-related Alzheimer Disease
- 210 Downloads
(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.
KeywordsDown syndrome GARS-AIRS-GART CP2 Astrocytic hypertrophy Oxidative stress Alzheimer’s disease LBP-1c/CP2/LSF
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.
- 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 18:6665–6672PubMedCrossRefGoogle Scholar
- Akiyama, Y (1998) “TFSEARCH: Searching Transcription Factor Binding Sites”. http://www.rwcp.or.jp/papia/
- 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 6:2043–2050PubMedCrossRefGoogle 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 1223–1256Google 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 39:179–185Google Scholar