Investigation of the role of tau gene transcription in neurodegeneration.
Doctoral thesis, UCL (University College London).
Thesis after 3 months minor corrections.pdf
Available under License : See the attached licence file.
Although the tau gene (MAPT) is not mutated in the majority of tauopathies, there are pathological disturbances in tau-isoform homeostasis. Investigation into MAPT linkage disequilibrium and haplotype structure, and the common variation of MAPT associated with increased risk of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) identified a possible basis for the disturbances in tau-isoform homeostasis. Of multiple haplotypes in the H1 clade, the H1c sub-haplotype drives the association with PSP and CBD, suggesting that it carries the pathogenic variation leading to increased risk of these largely sporadic disorders. The aim of this project was to investigate the regulation of the transcription of MAPT by first identifying transcription factors (TFs) and TF complexes that bind to the MAPT core promoter and its conserved regulatory domains. The specific aim was to determine if differential binding of TFs and TF complexes to the allelic variants of the SNPs in the MAPT promoter region forms the basis of the allele-specific differences in MAPT transcription and splicing that we have observed in vitro and in vivo. Results from electrophoretic mobility shift assays, pull-down experiments and mass spectrometry had shown potentially novel proteins binding to the disease-associated SNP under investigation. Bioinformatic analyses helped to stratify these proteins according to possible relevance. While immunoblotting alongside co-transfection of siRNA and luciferase promoter construct experiments had shown initial evidence of a complicated relationship between cis and trans factors within the tau promoter region. These findings were novel and they provide new insight into the regulation of one of the most important genes in neurodegeneration. The identification of MAPT transcriptional machinery would provide further insight into the role of MAPT in neurodegeneration and the basis for therapeutic intervention.
|Title:||Investigation of the role of tau gene transcription in neurodegeneration|
|Open access status:||An open access version is available from UCL Discovery|
|Keywords:||tau, neurodegeneration, Alzheimer's disease|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology|
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