Abstract
Lafora disease (LD), a fatal genetic form of myoclonic epilepsy, is characterized by abnormally high levels of cellular glycogen and its accumulation as Lafora bodies in affected tissues. Therefore the two defective proteins in LD-laforin phosphatase and malin ubiquitin ligase-are believed to be involved in glycogen metabolism. We earlier demonstrated that laforin and malin negatively regulate cellular glucose uptake by preventing plasma membrane targeting of glucose transporters. We show here that loss of laforin results in activation of serum/glucocorticoid-induced kinase 1 (SGK1) in cellular and animals models and that inhibition of SGK1 in laforin-deficient cells reduces the level of plasma membrane-bound glucose transporter, glucose uptake, and the consequent glycogen accumulation. We also provide evidence to suggest that mammalian target of rapamycin (mTOR) activates SGK1 kinase in laforin-deficient cells. The mTOR activation appears to be a glucose-dependent event, and overexpression of dominant-negative SGK1 suppresses mTOR activation, suggesting the existence of a feedforward loop between SGK1 and mTOR. Our findings indicate that inhibition of SGK1 activity could be an effective therapeutic approach to suppress glycogen accumulation, inhibit mTOR activity, and rescue autophagy defects in LD.
MeSH terms
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Animals
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Autophagy / drug effects
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Autophagy / genetics*
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Benzoquinones / pharmacology
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Biological Transport / genetics
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COS Cells
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Cell Line
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Chlorocebus aethiops
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Dual-Specificity Phosphatases / genetics*
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Enzyme Inhibitors / pharmacology
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Glucose / metabolism
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Glucose Transporter Type 1 / biosynthesis
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Glycogen / metabolism
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Immediate-Early Proteins / antagonists & inhibitors
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Immediate-Early Proteins / biosynthesis
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Immediate-Early Proteins / metabolism*
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Immunosuppressive Agents / pharmacology
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Lactams, Macrocyclic / pharmacology
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Lafora Disease / genetics*
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Mice
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Mice, Knockout
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Phosphorylation
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / metabolism*
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Protein Tyrosine Phosphatases, Non-Receptor
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RNA Interference
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RNA, Small Interfering
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / metabolism*
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Ubiquitin-Protein Ligases / genetics
Substances
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Benzoquinones
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Enzyme Inhibitors
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Glucose Transporter Type 1
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Immediate-Early Proteins
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Immunosuppressive Agents
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Lactams, Macrocyclic
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RNA, Small Interfering
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Glycogen
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NHLRC1 protein, mouse
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Ubiquitin-Protein Ligases
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases
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serum-glucocorticoid regulated kinase
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Dual-Specificity Phosphatases
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Epm2a protein, mouse
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Protein Tyrosine Phosphatases, Non-Receptor
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Glucose
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Sirolimus
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geldanamycin