Exogenous ketone bodies ameliorate neurodevelopmental defects associated with daf-18/PTEN mutations

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

Cordoba

Congreso; XXXV Reunión nual de La Sociedad Argentina de Investigación en Neurociencias; 2020

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a conserved signal transduction cascade involved in several processes, including neurodevelopment (ND). The lipid phosphatase PTEN inhibits the PI3K signaling to activate FOXO. PTEN mutations are strongly linked to ND disorders. Ketogenic diets (KGD) was proposed as a nutritional strategy for treating core symptoms of ND disorders. The mechanistic bases of these beneficial effects are not understood. The reduced availability of carbohydrates in KGD leads to ketone bodies production in the liver. The ketone body β-hydroxybutyrate (βHB) was reported to induce FOXO transcription factor in mammals. Taking advantage of its relative simple anatomy, genetics, high degree of conservation and short lifespan, we used the nematode C. elegans to mechanistically analyze the effects of βHB in PTEN (daf-18 in worms) mutants. In C. elegans, mutants in daf-18/pten also exhibit ND defects and fail to translocate DAF-16/FOXO to the nucleus. We found that exogenous βHB induces DAF-16/FOXO translocation in this nematode. Moreover, daf-18/pten mutants grown in the presence of βHB show enhanced behavioral responses in comparison with the controls. Taken together, these preliminary results support the hypothesis that the exogenous ketone body βHB could ameliorate ND defects caused by daf-18/pten mutations, and may constitute a first step in validating exogenous βHB as a potential novel pharmacological treatment for ND disorders.