Funded Projects

MAGEL2 is a gene frequently deleted or mutated in individuals affected with PWS. Furthermore, mice lacking MAGEL2 display symptoms similar to those seen in PWS children. However, a critical barrier to our understanding of MAGEL2’s link to PWS has been determining its function within cells. Recently, my group has solved this enigmatic question. We showed that MAGE-L2 functions to prevent aberrant degradation of proteins that normal reside in the plasma membrane. It does so through the specific modification of another protein, called WASH. This modification, termed ubiquitination, activates the WASH protein that facilitates recycling of proteins sparing them from aberrant degradation in the lysosome, the garbage can of a cell. In this proposal, we aim to determine whether MAGEL2’s function in endosomal recycling is observed in patient-derived primary neuronal cells that originate from dental pulp stem cells taken from discarded ‘baby teeth’. Furthermore, we aim to determine whether there is a genotype-to-phenotype relationship between the genetic causes of PWS (deletion or uniparental disomy; UPD), presence of autism spectrum disorder, and defects in endosomal trafficking. Finally, we aim to move beyond characterization of the cellular defects of PWS to explore proof-of-principle treatment strategies to rescue endosomal recycling pathways in the hope to discovering new therapeutic avenues.