Project Details
Projekt
Complex formation, dolichol (re)cycling and pathological mechanisms in the initial steps of the N-glycosylation pathway
Applicant
Privatdozent Dr. Christian Thiel
Subject Area
Cell Biology
Biochemistry
Biochemistry
Term
since 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 289991887
Congenital Disorders of Glycosylation (CDG) actually comprise more than 100 different inherited disorders in glycoconjugate biosynthesis in man which in general affect a variety of organs and are mostly combined with severe neurological impairment. Over the last few years we have identified a large number of patients suffering from a variety of early glycosylation deficiencies. Among these defects especially those occurring in mannosyltransferases localized at the cytosolic side of the ER lead to extremely severe clinical phenotypes. Although comprehensive biochemical analysis has demonstrated the dysfunction of the mutated protein responsible, more in-depth studies on regulatory mechanisms under N-glycosylation deficient conditions are lacking. Our project aims to investigate the pathophysiologic correlation between the ALG1, ALG2 and ALG11 mannosyltransferases in the early steps of the N-glycosylation pathway and the impact of their reduced functionality on other glycosylation pathways by investigating cellular and animal models with a focus on the bifunctional ALG2 mannosyltransferase. In particular we are interested to find out whether the sequential addition of mannose residues from GDP-Mannose onto a dolichol-bound acceptor oligosaccharide by ALG1, ALG2 and ALG11 is carried out while they are structurally associated with each other. Besides, we will determine how malfunctions of these mannosyltransferases change the composition of the three types of N-glycans (complex, hybrid and mannose-rich) and potentially influence O- and C-mannosylation as well as O-fucosylation. An additional aim of our work will be to perform studies to show whether shortened ALG2 transcripts account for alpha1,6 mannosyltransferase activity. In a Medaka model for ALG2-CDG we want to study Alg2-dependent processes as these are crucial for embryonic development. In addition to comprehensive analyses of the Alg2-Medakas to detect biochemical irregularities and organ abnormalities, we are also interested in detecting changes in the N-glycan composition and glycosylation site usage of Alg2-deficient embryos in comparison to wildtype animals.
DFG Programme
Research Units
