学术报告-2017-12-19

讲座内容：Discovery of mutations in O-GlcNAc transferase leading to X-linked intellectual disability

报告人： Daan van Aalten 教授（英国邓迪大学）

主 持 人：袁 凯 教授

时    间：2017年12月19日 上午10:00

地    点：中南大学医学遗传学研究中心老楼5楼学术报告厅

van Aalten教授现为英国Dundee大学生命科学院教授，博士生导师。多年来致力于O-GlcNAc糖基化分子机制的研究，是O-GlcNac研究领域的顶尖专家，在Science，Nature，Nature Chemical Biology, Nature Structural Molecular Biology, PNAS, eLife等杂志上发表170余篇高水平研究论文，被引用9000余次，篇均引用54次，H因子高达52。他先后获得EMBO long-term fellowship, Wellcome Trust Research Career Development Fellowship, 和Wellcome Trust Senior Research Fellowship等的资助，所获研究经费累计超过3000万英镑。并被授予EMBO Young Investigator Award, Lister Institute for Preventive Medicine Research Prize, Royal Society of Chemistry’s Dextra Laboratories Carbohydrate Award。2010年，被选为The Royal Society of Edinburgh的会士。2017年受聘为中南大学湘雅医院客座教授。

 

Abstract：X-linked intellectual disability is a broad spectrum of monogenic disease covering over 800 genes. We have discovered mutations in O-GlcNAc transferase, leading to X-linked intellectual disability and general developmental delay. Protein O-GlcNAcylation is a reversible posttranslational modification of Ser/Thr on nucleocytoplasmic proteins in metazoa. This modification is essential for life at the single cell level and regulates a range of cellular processes such as metabolism, transcription, translation and signalling pathways. Defects in protein O-GlcNAcylation have been linked to diabetes, cancer and neurodegenerative disease. However, the link between O-GlcNAcylation of specific proteins and these processes/diseases remains largely unexplored.  Deletion of the O-GlcNAc transferase (OGT) or O-GlcNAc hydrolase (OGA) genes in invertebrate/vertebrate models gives rise to lethality. Using the remarkable developmental phenotypes of the XLID patients and O-GlcNAc deficient Drosophila as a starting point, my lab is focused on discovering the O-GlcNAc proteins linked to these phenotypes, and the cellular processes involved, using a combination of chemical biology, structural biology, biochemistry and genetics. We have been the first to described the structures and mechanisms of the OGA and OGT enzymes. We have then exploited this detailed structural knowledge to design potent inhibitors, and applied these to study the effect of modulating cellular O-GlcNAc levels and the effects on specific signalling pathways. Currently we are developing novel tools for the enrichment and MS/MS identification of O-GlcNAc proteins from Drosophila embryos and are inducing hypo-O-GlcNAcylation and disease mutations by means of CRISPR/Cas9 gene editing technology and the delivery of specific OGT inhibitors to ultimately allow us to study the mechanisms behind individual O-GlcNAc sites.