O-GlcNAc signalling in (neuro) development and neurodegenerative disease

 

The activity of proteins in the cell is regulated by small chemical on/off switches. My lab works on one such switch, a sugar modification called O-GlcNAc. Several families have recently been discovered with inherited mutations affecting this process and leading to intellectual disability – we are trying to understanding how/why.

The modification of series/threonines on cytosolic proteins in higher eukaryotes with O-linked N-acetylglucosamine (O-GlcNAc) is an essential, abundant and dynamic post-translational modification. O-GlcNAc has been implicated in a wide range of cellular processes, including transcription, the cell cycle, signal transduction networks and protein folding, and shows interplay with regulatory protein phosphorylation. Despite recent biochemical and structural advances, our understanding of the precise functional implications of O-GlcNAc is still limited and we do not understand how O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (OGA), single essential genes in metazoa, together build the dynamic O-GlcNAc proteome. Interestingly, O-GlcNAc appears to be particularly abundant in the brain and recent proteomics studies have identified O-GlcNAc on proteins that are involved in the development and progression of neurodegenerative diseases – Tau in Alzheimer’s disease, the PrP prion protein in Creutzfeldt-Jakob disease and a-synuclein in Parkinson’s disease. Furthermore, mutations in the OGT gene give rise to X-linked intellectual disability.

My lab aims to transform our understanding of the mechanisms, regulation and functional implications of the O-GlcNAc modification in the brain and neurodegenerative disease using a combination of chemical, biochemical, structural, cell biological and genetic approaches. Recently we have been using CRISPR-Cas9 genome editing in stem cells, Drosophila and vertebrate models to explore the effects of OGT catalytic activity on development and disease.