Effects of Nf1 on sleep behavior are mediated through starvation caused by deficits in SARM1 dependent NAD+ metabolism

Neurofibromatosis 1 (NF1) is a relatively common autosomal dominant disease which predisposes to the formation of tumors, and is also associated with behavioral phenotypes, including sleep disturbances. As loss of the NF1 protein has been recently associated with metabolic dysfunction, we explored the relationship between metabolic and behavioral phenotypes through metabolomic analysis of Drosophila Nf1 -null mutants. Nf1 -null mutants exhibit a metabolic signature indicative of starvation, with diminished metabolites related to glucose, glycogen, and fatty acid processing and increased mRNA of Akh , a hormone that promotes foraging during starvation. Reduced sleep in Nf1 -null mutants was rescued by genetic manipulation of the AKH pathway and by a high-sucrose diet, which also partially corrected hypolipidemia, suggesting that sleep loss is due to starvation-induced foraging. Interestingly, behavioral phenotypes can be recapitulated by loss of NF1 only in the periphery and trace to mitochondrial defects that include elevated levels 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, setting the scene for new pharmacological and dietary approaches that could provide relief to NF1 patients.