Kay, VA; (2013) Cellular minigene models for the study of allelic expression of the tau gene and its role in progressive supranuclear palsy. Doctoral thesis , UCL (University College London).

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Abstract

Progressive supranuclear palsy (PSP) belongs to a group of neurodegenerative disorders that are characterised by hallmark pathology consisting of intra-neuronal aggregates of the microtubule-associated protein, tau. In PSP, these aggregates are almost exclusively composed of one of the two major tau protein isoform groups normally expressed at similar levels in the healthy brain, indicating a role for altered isoform regulation in PSP aetiology. Although no causal mutations have been identified, common variation within the gene encoding tau, MAPT, has been highly associated with PSP risk. The A-allele of the rs242557 single nucleotide polymorphism has been repeatedly shown to significantly increase the risk of developing PSP. Its location within a distal region of the MAPT promoter region is significant, with independent studies – including this one – demonstrating that the rs242557-A allele alters the function of a transcription regulatory domain. As transcription and alternative splicing processes have been shown to be co-regulated in some genes, it was hypothesised that the rs242557-A allele could directly affect MAPT alternative splicing through its differential effect on transcription. This project describes an investigation into the molecular mechanism linking the MAPT association with the tau isoform dysregulation characteristic of PSP. The design, construction and in vitro investigation of minigenes representing common MAPT variants will be presented in detail and will demonstrate that promoter identity plays an important role in regulating the alternative splicing of MAPT transcripts. The specific role of the rs242557 polymorphism in MAPT transcription and splicing are investigated and the two alleles of the polymorphism are shown to differentially influence these two molecular processes, providing a plausible mechanism linking the two phenomena known to be associated with PSP – a common genetic variant within the MAPT promoter region and detrimental changes to tau isoform production.

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