Neuronal Mechanisms of Neurofibromin-Mediated Modulation of Metabolic Homeostasis

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PROJECT SUMMARY/ABSTRACT Neurofibromatosis type 1 is a common monogenic developmental disorder, affecting 1 in 3,000 individuals worldwide. Neurofibromatosis type 1 is a progressive developmental disorder caused by mutations in the NF1 gene, which encodes for the protein neurofibromin (Nf1). Neurofibromatosis type 1 patients are predisposed to developing a range of complications, including peripheral nerve associated neurofibromas, malignant tumors, skeletal abnormalities, reduced overall growth, and neurocognitive deficits. These complications significantly affect patients’ quality of life and contribute to the overall decreased life expectancy of those with the disease. Emerging studies suggest that mutations in NF1 may alter metabolism; neurofibromatosis type 1 patients exhibit multisystemic symptoms and abnormalities such as short stature, pituitary growth hormone deficiencies, and reduced body mass indexes. However, the mechanism by which Nf1 modulates metabolism is unknown. My recently published data suggest that Nf1 regulates metabolism via a discrete neuronal circuit, creating the opportunity to study the mechanisms of Nf1-mediated neuronal control of metabolism. Here, I propose to elucidate the mechanisms by which Nf1 regulates neuronal activity, leading to metabolic dysregulation and contributing to neurofibromatosis type 1 disease pathophysiology when mutated. Experiments will leverage the well-established Drosophila model of neurofibromatosis type 1, its highly conserved signaling pathways, and the organism’s experimental and genetic power to study the novel interactions between Nf1, neuronal circuit activity, and metabolism. This research will identify the key signaling pathway activated by Nf1 to regulate metabolism within neurons (Aim 1) and test the effects of Nf1 on neuronal and circuit physiology, leading to metabolic dysregulation (Aim 2). This will be achieved using a comprehensive and powerful combination of genetics, neural circuit analysis, and novel functional in vivo imaging. In sum, the proposed research is among the first studies to use optical imaging to study a central neuronal circuit that has been shown to regulate metabolism and provide a detailed dissection of the neural circuits mediating Nf1 metabolic effects. Importantly, discerning the effect of Nf1 on metabolic rate will be essential in understanding the multisystemic symptoms of neurofibromatosis type 1, particularly those controlled by the central nervous system, and provide critical information on the link between Nf1 and metabolism.