Tau tangles are the most prevalent pathology in neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), and the tau (MAPT) region is genetically associated with these diseases. Large gaps in our knowledge remain regarding how neurodegenerative disease-linked tau mutations and MAPT variation promote tau aggregation and neurodegeneration. In European populations, the MAPT gene variation exists as two types, H1 (~90%) and H2 (~10%). AD, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) show associations with H1, whereas Picks disease (PiD) has an H2 association. However, the effects of this MAPT association on tau expression and splicing are currently unknown.
In the past, we have been dependent on short-read DNA and RNA sequencing, but this has significant limitations. Short reads cannot fully assemble complex genomic rearrangements, especially repetitive sequences, nor can they accurately identify or quantify expressed RNA-differences (isoforms) as in the MAPT locus. To overcome these limitations, we have established a cutting-edge long-read sequencing facility with a range of genomic/transcriptomic techniques and analysis pipelines that we will use to investigate the MAPT locus in 12 brains from controls, AD, PSP, CBD, PiD and FTD (mutation and nonmutation cases) from four different brain regions. Additionally, we also will analyze neurons and organoids derived from induced pluripotent stem cells (iPSCs) with and without splicing mutations in MAPT, enabling us to understand the regulation of neuronal expression, validating an in vitro model to test novel therapies to modify tau expression. We will investigate splicing and allele-specific expression of MAPT in brains and iPSC lines, compared with controls and using these data, reassess genome sequencing in the dementia patients for previously hidden mutations. This will enable a complete understanding of the MAPT locus, expression and splicing across neurodegeneration and iPSC-derived lines, generating a sharable resource to drive the identification of novel therapeutic targets.