University of Dundee

MRC DTP 4 Year PhD Programme: O-GlcNAcylation and protein (mis)folding

This project is offered as part of the University of Dundee 4-year MRC DTP Programme “Quantitative and Interdisciplinary approaches to biomedical science”. This PhD programme brings together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science.  The outstanding biomedical research at the University of Dundee was recognised by its very high rankings in REF 2014, with Dundee rated as the top University for Biological Sciences in the UK.  A wide range of projects are available within this programme crossing exceptional strengths in four key areas: Infection and Disease; Responses to Cellular Stresses; Development, Stem Cells and Neurobiology; and Big Data and Translation.  All students on this programme will receive training in computational biology, mathematical biology and statistics to equip with the quantitative skills in tackling complex biological questions.  In the 1st year, students will carry out 3 rotation projects prior to selection of the final PhD project.

Protein O-GlcNAcylation, catalysed by O-GlcNAc transferase (OGT), is an essential posttranslational modification that has been shown to be indispensable for embryogenesis and early development through mechanisms that remain to be explored. Very recently the van Aaltenlab has identified OGT mutations in several families that segregate with severe intellectual disability, developmental delay and motor dysfunction.Preliminary data suggest that the O-GlcNAc modification may contribute to proper folding of proteins, with links to Alzheimer’s disease (Tau), Parkinson’s disease (synuclein) and ALS (TDP-43). Ourvision is to for the student touncover the O-GlcNAc-dependent molecular and biological mechanisms that contribute to solubility/folding of functional proteins that otherwise contribute to proteinopathies, including the TDP43 protein that is the focus of the McGurk lab. Using a highly multidisciplinary approach, the student will useDrosophilagenetics, neurobiology and biochemistryto uncover the molecular, biochemical and cellular mechanisms underpinning the links between O-GlcNAc and neurodevelopment/neurodegeneration. Specifically, the student will have the following aims (with significant preliminary data:

1) To generate rationally designed OGA/OGT mutants with limited catalytic activity in DrosophilausingCRISPR/Cas9 and phenotypically characterise the effect of reduced OGA/OGT activity on the developing and ageing brain.

2) Perform genetic-modifier screens in fly models of neurodegenerative disease (including Tau, synuclein and TDP-43 overexpression models) combined with in vitro protein assays to determine if OGA/OGT activity functionally regulates the (mis)folding of theseproteins.

3) To use the OGA/OGT mutant flies to conduct a genetic screen, preferably by random mutagenesis, to uncover factors that are key nodes in the mechanistic link between OGT, brain function and (mis)folding of these disease-causing proteins.

Recent work from the lab can be found in the following references:

V.M. Pravata, V. Muha, M. Gundogdu, A.T. Ferenbach, P. Kakade, V. Vandadi, A.C. Wilmes, V.S. Borodkin, S. Joss, M.P. Stavridis andD.M.F. van Aalten, "O-GlcNAc transferase catalytic deficiency in twins with X-linked intellectual disability",Proc.Natl.Acad.Sci.USA, (2019), 116, 14961-14970.

M. Gundogdu, S. Llabrés, A. Gorelik, A.T. Ferenbach, U. Zachariae andD.M.F. van Aalten, "The O-GlcNAc transferase intellectual disability mutation L254F distorts the TPR helix",Cell Chem.Biol.(2018), 25, 513-518.

McGurk, Leeanne et al.Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization,Molecular Cell, Volume 71, Issue 5, 703 -717.e9