PhD Studentship: Investigating Tau (MAPT) Locus, the Major Component of Neurofibrillary Tangles in Dementia

PhD Studentship/Fellowship, ARUK funded

Investigating tau (MAPT) locus, the major component of neurofibrillary tangles in dementia

Project Description

Tau tangles are the most prevalent pathology in neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The tau (MAPT) locus is genetically associated with these diseases. Large gaps in our knowledge remain regarding how various FTDP-17 linked mutations and MAPT haplotype promote tau aggregation and neurodegeneration. In European populations this MAPT locus exists as two clades, H1 (~90%) and H2 (~10%). Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and AD show associations with the H1 haplotype, whereas Picks disease (PiD) has an H2 association. However, large gaps in our knowledge remain regarding how FTDP-17 linked tau mutations and MAPT haplotype promote tau aggregation and neurodegeneration, and the effects of the MAPT haplotype on tau expression and splicing; fundamental questions in understanding MAPT related neurodegeneration.

Over the last 3-years we have established the UCL Long-Read Sequencing facility with the development of a range of genomic/transcriptomic techniques and analysis pipelines. In this proposal we will (i) investigate the MAPT locus and flanking regions in 12 genotyped AD, FTD, PSP, CBD, PiD (mutation and non-mutation cases) and control samples (four brain regions in each). (ii) Analyse neurons, astrocytes and organoids derived from induced pluripotent stem cells (iPSC) with and without mutations in MAPT, enabling us to understand the regulation of tau expression during neuronal development, validating an in-vitro model that could be used to test novel therapies to modify tau expression. (iii) In each brain region/iPSC line match long-read RNA with DNA sequencing, and with short-read Illumina sequencing, (iv) Investigate splicing and allele specific expression (MAPT mutations and haplotype) in different neurodegenerative disease brains, iPSC lines and brain regions compared with controls and (v) Reassess whole genome sequencing in the dementia cohorts of the 100,000 genomes and Queen Square dementia series for variation in previously misannotated regions of the MAPT gene.

Duration. Full-time: 4-year studentship/fellowship, starting from May 2024.

Academic Supervisors: Profs Henry Houlden and John Hardy.

Funding

PhD stipend of £21,000 per year, for 4 years.

UK home PhD fees paid and lab consumables. Overseas applicants welcome, but will be required to pay the international tuition fee balance.

The successful candidate will be a highly motivated individual who can work both independently and as part of a team. Applicants must hold a biological or medical degree or a related subject as or candidates should have (or expect to achieve) a minimum of a 2.2 Honours BSc degree or MD/medical degree or MBBS or MSc. Please email any queries to [email protected] and [email protected]

Location

UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG

Closing Date

3 weeks after posting

To apply, please send a cover letter and CV to [email protected] and [email protected]

Shortlisted candidates will be interviewed.