University of Dundee

The link between O-GlcNAc signalling and neurodevelopmental disease

Glycosylation of serines/threonines with O-linked N-acetylglucosamine (O-GlcNAc) on nucleocytoplasmic proteins in higher eukaryotes is an abundant and dynamic intracellular post-translational modification that is essential for metazoan life. O-GlcNAcylation has been implicated in a wide range of cellular processes and its dysregulation has been linked to neurodegeneration, diabetes and cancer. Work in the van Aalten lab is aimed at understanding how only two single metazoan proteins, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), together build the cellular O-GlcNAc proteome and which O-GlcNAcylated proteins are linked to the severe developmental phenotypes of the ogt gene disruption mutants in mice, zebrafish, Xenopus and Drosophila.
   Very excitingly, working together with clinicians we have recently discovered point mutations in the OGT gene that segregate with a neurodevelopmental disorder. Patients suffer from severe intellectual disability, behavioural problems and musculoskeletal deformities. Your PhD project will uncover the mechanistic biology underlying this disease. We have access to patient material and using CRISPR/Cas9 we have already generated these disease mutations in animal model systems. Depending on your interests you will take genetic, cell biological, biochemical and/or structural approaches in a multi-disciplinary environment to understand how these mutations are linked to dysfunction of specific O-GlcNAc target proteins. Please contact Prof. Daan van Aalten (dmfvanaalten@dundee.ac.uk) to informally discuss this project.