PhD opportunity

Targeted dephosphorylation of hyperphosphorylated TAU in Alzheimer’s disease

Funding availability

Unfunded

Application deadline

31 August 2026

  • Funding – self-funded/externally sponsored applicants   (PhD Fees can be found here)
  • Applications are accepted year round
  • Standard Entry dates – January and September
  • Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder. Despite several decades of preclinical and clinical research, few effective therapeutic approaches exist against AD. Thus, there is a pressing need to develop innovative therapeutic approaches against AD. A key hallmark of AD is the intracellular aggregation of the Tau protein in neurofibrillary tangles (NFTs). Hyperphosphorylation of Tau is a characteristic feature in the pathogenesis and progression of AD. Several kinases are known to phosphorylate Tau, while protein phosphatase 2A (PP2A) is known to dephosphorylate Tau. Hyperphosphorylation of Tau is thought to be a pathological driver for AD, and hence its reversal is a potential therapeutic approach. Inhibition of Tau kinases or activation of PP2A can potentially reverse Tau hyperphosphorylation but these would also cause many undesired off-target effects. An innovative strategy would be to selectively target the dephosphorylation of the hyperphosphorylated Tau by recruiting protein phosphatase activity to Tau. The Sapkota laboratory has recently developed the affinity-directed phosphatase (AdPhosphatase) system for targeted dephosphorylation of endogenous proteins. This project seeks to use the AdPhosphatase system for targeted Tau dephosphorylation and investigate the role of Tau hyperphosphorylation in Tau aggregation. Subsequently, the project seeks to leverage on reported Tau and PP2A or other phosphatase ligands to develop small bivalent molecules (which we refer to as Phosphatase TArgeting Chimeras, or PhosTACs) that serve to recruit endogenous PP2A or other phosphatase activity to phospho-Tau to induce Tau dephosphorylation. Successful demonstration of targeted Tau dephosphorylation and its consequence in inhibiting or reversing aggregation could uncover Tau PhosTACs as potential therapeutic agents against AD. 

The successful PhD student will be based within the Sapkota lab at the MRC Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU) (http://www.ppu.mrc.ac.uk/). The student will employ cutting-edge CRISPR/Cas9 genome editing and mass-spectrometric technologies as well as state-of-the-art blend of molecular, biochemical, cell biology and chemical methodologies. MRC-PPU collaborates with three leading pharmaceutical companies (Boehringer Ingelheim, GlaxoSmithKline, Merck Serono) through the long-running Division of Signal Transduction Therapy (DSTT) collaboration. As this project is expected to uncover a new way of targeting the dephosphorylation of specific phospho-protein targets, this collaboration will enable us to expedite the translation of our findings and tools into potential drug discovery projects.

Reference:

Simpson LM, Fulcher LJ, Sathe G, Brewer A, Zhao JF, Squair DR, Crooks J, Wightman M, Wood NT, Gourlay R, Varghese J, Soares RF, Sapkota GP (2023) An affinity-directed phosphatase, AdPhosphatase, system for targeted protein dephosphorylation. Cell Chem Biol. 2023 Feb 16;30(2):188-202.e6. doi: 10.1016/j.chembiol.2023.01.003. Epub 2023 Jan 30. PMID: 36720221

Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research.  We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.

How to apply

Please contact the principal project supervisor to discuss your interest further, see supervisor details below.

For general enquiries, contact [email protected]

Supervisors

Principal supervisor

Second supervisor