The role of metabolism in a Drosophila model of Neurofibromatosis 1

Intellectual disability (ID) is a prevalent condition affecting 2.5% of the global population, oftenpresenting alongside sleep and circadian behavior disturbances. Neurofibromatosis 1 (NF1) serves as a prominent example of a monogenic intellectual disability syndrome (MIDS) which commonly leads to disrupted sleep behavior and has been recently associated with metabolic dysfunction. In this study, we investigated the sleep disturbances and metabolic dysfunctions associated with NF1 through metabolomic analysis of Drosophila Nf1 -null mutants. We found that these mutants display a metabolic signature indicative of starvation„ characterized by diminished metabolites related to glucose, glycogen, and fatty acid metabolism, along with elevated mRNA levels of Akh, a hormone that stimulates foraging behavior during starvation. Sleep behavior was rescued by genetic manipulation of the AKH pathway and also by a high-sucrose diet, which also partially corrected hypolipidemia in Nf1-null mutants, suggesting that sleep loss is due to starvation-induced foraging. Interestingly, behavioral phenotypes can be recapitulated by loss of NF1 in the periphery and trace to mitochondrial defects that include elevated activity of the NADase SARM1. Indeed, inhibition of SARM1 activity rescues sleep behavior in Nf1 -null flies. These findings suggest a novel connection between loss of NF1 and mitochondrial dysfunction caused by SARM1 hyperactivation. Our work opens up new avenues for research into pharmacological and dietary interventions in NF1, and also potentially offer a schematic for investigation of the role of metabolosim in other MIDS.