Disrupting FBXW11-mediated degradation of NF1 to rescue haploinsufficiency

Studies in NF1 mouse models have revealed that these animals develop learning and behavioral problems similar to human patients and thus provide a valuable resource to study the disease and develop new and improved treatment strategies. In this project, we propose a new and innovative approach to treating learning and behavioral deficits in NF1 by boosting levels of the neurofibromin protein within the brain. We have discovered a new and important mechanism by which neurofibromin is regulated within the cell by interacting with another protein that marks neurofibromin for degradation. Further, we have shown that genetic disruption of that gene can restore neurofibromin protein levels within key brain areas that are responsible for the development of learning and behavioral disorders associated with NF1. A primary goal of this project is to better understand the signaling pathways that trigger neurofibromin for its degradation. If these studies are successful, they will provide the necessary justification to advance new gene and drug-based therapies to clinical trials for the treatment of learning disabilities and behavioral disorders in NF1.