Functional significance of haplotype-specific variations in MAPT and their potential role in the pathogenesis of neurodegenerative disease. (360G-Wellcome-075406_Z_04_A)

Functional significance of haplotype-specific sequence variations in MAPT and their potential role in the pathogenesis of neurodegenerative disease With a rapidly ageing population in many developed countries, the study of neurodegenerative illness and dementia is becoming increasingly important. A whole range of neurodegenerative diseases, collectively referred to as tauopathies, is characterised by the presence of aggregated microtubule-associated protein tau in selected brain regions. Some sporadic tauopathies, in particular progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), have been linked to haplotype-specific sequence variations in the locus of the microtubule-associated protein tau (MAPT) gene. Two major haplotypes seem to exist in the population (H1 and H2), with H1 being overrepresented in PSP and CBD. The reasons for this association of H1 with tauopathic diseases are still obscure. One possibility is that polymorphisms in H1 disrupt alternative splicing of tau pre-mRNA. This project proposes to investigate the functional significance to the haplotype-specific sequence variations in MAPT and their role in conferring susceptibility to neurodegenerative disease. This will involve three specific aims: Aim 1: Create cellular models of the H1 and H2 haplotypes to test their effect on alternative splicing and thus throw light onto their potential role in the development of neurodegeneration. Aim 2: Create and characterise improved transgenic mouse models carrying the wild-type genomic loci of the H1 and H2 MAPT variants and recombinants thereof. Aim 3: Modelling the interaction between genetics and environment by testing whether the H1 haplotype renders organisms more susceptible to environmental influences associated with the risk of developing neurodegenerative disease.