Glucose is stored in specialized tissues (mainly liver and muscle) in the form of a branched polymer called glycogen. Glycogen Synthase is the only enzyme able to catalyze this polymerization and its two isoforms (LGS and MGS) are mainly expressed in liver and in muscle, respectively. However, MGS is also expressed in all other tissues, regardless of their limited capacity to produce Glycogen. MGS activity is tightly controlled by several mechanisms. Recent results from the receiving group show that demise of these mechanisms in neurons causes apoptosis and may be the cause of Lafora disease. Our working hypothesis is that deregulation of MGS protein levels and/or activity is causative of several pathologies. Therefore, we aim to dissect the consequences of the loss of regulation of MGS in several cell types and tissues, using a state-of-the-art genetic approach. Our results will bring new evidence for the understanding of many unresolved human health conditions, and help to identify potential therapeutical strategies. The specific research objectives are: 1. To elucidate the mechanism by which the accumulation of glycogen triggers apoptosis. 2. To study whether aberrant accumulation of glycogen is responsible for some degenerative conditions. 3. To establish whether GS has a moonlighting function. These questions will be addressed both in vitro, using cell culture and diverse cell biology techniques, and in vivo, using newly available conditional mouse models. The applicant will join a group of reference in the study of the metabolism of glycogen, and will offer his extensive experience in the generation and use of mouse models for human disease. It is the applicant’s aim to become a skilled, independent research manager, either as a group leader or as scientific manager for research institutions. This project will provide the applicant with excellent scientific and managerial training opportunities.