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.
Department of Biological Sciences & Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Navodita
N
Jain
Department of Biological Sciences & Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Rohit
R
Mishra
Department of Biological Sciences & Bioengineering, Indian Institute of Technology, Kanpur 208016, India. Electronic address: sganesh@iitk.ac.in.
Subramaniam
S
Ganesh
D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D015536:Down-Regulation; D054637:Dual-Specificity Phosphatases / Q000378:metabolism*; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D020192:Lafora Disease / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D054558:Protein Tyrosine Phosphatases, Non-Receptor
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor
Autophagy; Epilepsy; Neurodegeneration; Post-translational modification; Transcriptional regulation