Structural and functional characterization of H2 haplotype MAPT promoter: Unique neurospecific domains and a hypoxia-inducible element would enhance rationally targeted tauopathy research for Alzheimer's disease

Bryan Maloney, Debomoy K. Lahiri

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Extraneuronal plaque comprising mostly the amyloid β peptide and intraneuronal tangles of hyperphosphorylated microtubule-associated τ protein (τ, gene . MAPT) are typical of AD. Misfolded τ is also implicated in Parkinson's disease and frontotemporal dementia. We aim to understand the regulation of the human . MAPT promoter by mapping its functional domains. We subcloned a 4868 base pair (bp) fragment from human BAC RPCI-11 100C5. Sequence analysis revealed an H2 haplotype . MAPT promoter, 5'-UTR, and intronal fragment. Database analysis of the fragment showed 50%-75% homology with mouse and >. 90% with rhesus monkey. Comparison with human H1 sequences revealed differences that crossed predicted transcription factor sites. DNA-protein interaction studies by electrophoretic mobility shift assay suggested hypoxia response and an active specificity protein 1 (SP1) site in the 5'-untranslated region. Transfection of a series of . MAPT promoter deletions revealed unique functional domains. The distal-most had different activities in neuronal vs. non-neuronal cells. We have cloned, sequenced, and functionally characterized a 4868. bp fragment of the human . MAPT 5'-flanking region, including the core promoter region (-. 302/+4), neurospecific domains (-. 4364/-1992 and +. 293/+504, relative to +. 1 TSS), and a hypoxia-inducible element (+. 60/+84). Our work extended functional analysis of the . MAPT sequence further upstream, and explores cell-type specificity of . MAPT promoter activity. Finally, we provided direct comparison of likely transcription factor binding sites, which are useful to understand differences between H1/H2 pathogenic associations.

Original languageEnglish (US)
Pages (from-to)63-78
Number of pages16
JournalGene
Volume501
Issue number1
DOIs
StatePublished - Jun 10 2012

Keywords

  • Cell type specificity
  • Gene regulation
  • H2 haplotype
  • Neurofibrillary tangles
  • Promoter
  • Tau

ASJC Scopus subject areas

  • Genetics

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