Dr. Moine aims to elucidate the role of DGKk in PWS pathology and explore its potential as a biomarker and therapeutic target. Recent evidence suggests that SNORD116 may regulate the expression of DGKk, an enzyme crucial for lipid signaling pathways in neurons. DGKk controls the balance between diacylglycerol (DAG) and phosphatidic acid (PA), influencing neuronal function, metabolism, growth and behavior. The study will employ an advanced mass-spectrometry technique called parallel reaction monitoring with stable isotope standards (PRM-SIS) to achieve highly sensitive and absolute quantification of DGKk in cells and tissue extracts of various PWS models. This research will accurately determine the importance and significance of DGKk alterations in PWS and help demonstrate DGKk's contribution to PWS pathology. These findings could lead to improved stratification of PWS presentations and open new avenues for personalized treatment strategies, potentially enhancing clinical outcomes for individuals with PWS.
Lay Abstract
This study aims to investigate the implication of a gene potentially important for Prader-Willi Syndrome called DGKk (diacylglycerol kinase kappa) and explore its potential as a biomarker of the disease. PWS has been associated with the loss of a region on chromosome 15 that expresses small RNA molecules called SNORD116. While the function of these SNORD116 molecules is not fully understood, emerging evidence suggests they regulate the expression of DGKk - an enzyme critical for neuronal lipid signaling, which controls the balance between two signaling molecules: diacylglycerol (DAG) and phosphatidic acid (PA). Thus, DGKk plays an important role in modulating neuronal signaling, metabolism, and behavioral regulation. Preliminary data suggest that DGKk is abnormally expressed in PWS models, providing a possible mechanism for the loss of SNORD116. However, the extent of DGKk dysregulation in PWS remains unclear due to limitations in current detection methods. This study will use advanced mass-spectrometry techniques to achieve highly sensitive and absolute quantification of DGKk in cells and tissue extracts from various PWS models. We will measure DGKk protein levels and activity in several brain regions of interest in PWS mouse models, particularly the SNORD116-KO model, and we will investigate DGKk alterations in a neuronal model derived from PWS patient cells (iPSCs). Overall, this research will determine the importance and significance of DGKk alterations in PWS and help demonstrate its contribution to PWS pathology. These findings may improve understanding of symptom variability in PWS and open new avenues for personalized treatment strategies.