In the last three decades, the discovery of inherited gene defects in the familial forms of Alzheimers disease (AD), Parkinsons disease (PD) and frontotemporal dementias with parkinsonism (FTLD-tau) and the study of the functions of their proteins within the context of the healthy and diseased neural cells has resulted in great leaps in our understanding of the pathogenic processes involved in these disorders. 

My primary research interest is the role of the tau gene (MAPT) and protein in neurodegeneration. MAPT, is mutated in familial FTLD-tau. Insoluble fibrillar aggregates of the microtubule-binding protein, tau (tangle pathology) characterise the intraneuronal pathological inclusions that are hallmarks of the large group of related neurological disorders called the tauopathies, which include AD and FTLD-tau, and the parkinsonian disorder, progressive supranuclear palsy (PSP). MAPT mutations affect either the microtubule-binding capacity, fibrillogenicity or the production of tau protein isoforms. In addition to inherited mutations it has been shown that common genetic variation in MAPT in the form of the H1 increases risk of PSP and corticobasal degeneration (CBD). We identified H1c, a sub-haplotype of H1, that accounts for the increased risk, with H1c causing higher MAPT transcription and production of the more fibrillogenic four-repeat isoforms of tau (4R-tau). We also identified a novel class of long non-coding RNA genes (MIR-NATs), paired with protein coding genes, including MAPT-AS1 at MAPT, that regulate gene expression by mediating ribosomal mRNA recruitment. In collaboration with Eisai Ltd, development of monoclonal antibodies targeting the microtubule-binding repeat domain of tau, led to E2814, a humanised anti-tau antibody that is currently in clinical trials for passive immunotherapy in AD. Current research also extends to proteostasis and the role of the unfolded protein response in tauopathies and understanding the structural basis of the diversity of four-repeat tau seeding strains.