Exogenous ketone bodies ameliorate behavioral defects associated with DAF-18/PTEN mutations

GIUNTI, S.; AZCONA, P.; DE ROSA, M.J.; RAYES, D.H.

Rosario

Congreso; SEcond LAtin American Worm meeting; 2020

The phosphatidylinositol3-kinase (PI3K) signaling pathway is a conserved signal transduction cascadeinvolved in several processes, including neurodevelopment. The lipidphosphatase DAF-18/PTEN inhibits the PI3K signaling pathway to activateDAF-16/FOXO. Mutations in DAF-18/PTEN impair neurodevelopment from worms tomammals due to DAF-16/FOXO inactivation. In humans, for instance, mutations inPTEN are strongly associated with autism spectrum disorders. During the last few years,growing evidence supports low-carbohydrate high-fat ketogenic diets (KGD) asnutritional strategies for treating core behavioral symptoms ofneurodevelopmental disorders. The mechanistic bases of these beneficial effectsare not understood. The reduced availability of carbohydrates in KGD leads toketone bodies (β-hydroxybutyrate (βHB) and acetoacetate) synthesis as an energysupplement to the brain. Recently, βHB has been reported to induce FOXOtranscription factor in mammals. We found that exogenous βHB also inducesDAF-16/FOXO translocation in C.elegans. The fact that FOXOactivation is crucial for neurodevelopment throughout the animal kingdom,raises the exciting possibility that exogenous βHB could mitigate behavioral defectsassociated with neurodevelopmental disorders. We here found that daf-18 mutants exhibitan inefficient escape response upon mechanical stimulation. Strikingly, thesedefects are ameliorated when these mutant animals were exposed to βHBthroughout development. This suggests that the ketone body βHB can reduceneurodevelopmental defects caused by daf-18mutations. We are now focused on analyzing whether daf-18 mutations lead to neuronalmorphology aberrations in the escape circuit, and whether βHB can reduce thesedefects. Moreover, we plan to recapitulate human pten mutationsassociated with neurodevelopmental disorders in C. elegans and analyze the effects ofketone bodies. We also plan to evaluate whether βHB can rescuephenotypes in other mutants with compromised neurodevelopment.Our experiments willcontribute to understanding the molecular mechanisms underlying KGD effects onneurodevelopmental disorders and may constitute a first step in validating βHBas a novel pharmacological treatment for these pathologies.