FoxO3a-mediated autophagy is down-regulated in the laforin deficient mice, an animal model for Lafora progressive myoclonus epilepsy

Lafora disease (LD) is an autosomal recessive disorder characterized by epileptic seizures, neurodegeneration and accumulation of polyglucosan bodies (Lafora bodies), arising due to defects in either the laforin protein phosphatase or the malin ubiquitin ligase. Among the multiple cellular pathways affected in LD, the specific cause of the autophagy blockade remains unknown. The autophagy impairment however is known to precede the formation of Lafora bodies in the LD mice models. We show here the involvement of a transcription factor, FoxO3a, to be a possible cause for the autophagic defect in cellular and animal models of LD. We find that the expression levels of FoxO3a and its targets Map1LC3b and Atg12 to be at lower levels in laforin-deficient cells and mice. We also find FoxO3a to be regulated indirectly by laforin through the activity of serum/glucocorticoid induced kinase, SGK1. Our results suggest that FoxO3a exerts a negative control over mTOR, and its loss could result in autophagic defects in LD associated with laforin deficiency. [Display omitted] •Loss of laforin results in reduced levels of Foxo3a.•Foxo3a targets Map1LC3b and Atg12 are also reduced in laforin-deficient cells.•Overactive SGK1 negatively regulates Foxo3a in laforin-deficient cells.•Enhancing Foxo3a partiality restores autophagy defect in laforin-deficient cells.