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Cited by 43Glycogen Storage Diseases and MyoclonusMetabolism, Diabetes, and CancerBiomedical Research and Pathophysiology

Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease

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Singh, Pankaj Kumar, Singh, Sweta, Ganesh, Subramaniam·2013·Molecular Biology of the Cell
DOI 10.1091/mbc.e13-05-0261PMC PMC3861076
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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.

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  • In Lafora disease, inhibiting SGK1 might be an effective therapeutic strategy to curb glycogen accumulation, suppress mTOR activity, and rectify autophagy defects.

    “Inhibiting SGK1 might be an effective therapeutic strategy to curb glycogen accumulation, suppress mTOR activity, and rectify autophagy defects in Lafora disease”

    From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Singh et al., 2013

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Cited by

Sorted by citations

Authors
Singh, P. K., Singh, S., & Ganesh, S.
Affiliations
Indian Institute of Technology Kanpur (IN)
Corresponding author
Ganesh, Subramaniam
ORCID
Venue
Molecular Biology of the Cell
Publisher
American Society for Cell Biology (ASCB)
Published
2013-12-15
Volume
24
Issue
24
Pages
3776-3786
ISSN
  • 1059-1524 (ISSN-L)
  • 1939-4586
DOI
10.1091/mbc.e13-05-0261
PMC
PMC3861076
OpenAlex
W2118863420
Cited by
43
References
6
Citations by year
2026: 1 · 2025: 2 · 2024: 4 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 7 · 2018: 5 · 2017: 3 · 2016: 6 · 2015: 3 · 2014: 1 · 2012: 1
FWCI
2.73
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • Molecular Biology of the Cell (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
Council of Scientific and Industrial Research, India
Topics
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Biomedical Research and Pathophysiology
Keywords
Lafora disease, SGK1, laforin, malin, glycogen accumulation, Lafora bodies, glucose uptake, glucose transporters, mTOR, autophagy, myoclonic epilepsy, feed-forward loop
MeSH terms
Serum-Glucocorticoid Regulated Kinases, Animals, Autophagy, Biological Transport, Cell Line, Chlorocebus aethiops, Enzyme Inhibitors, Glucose, Glycogen, Immunosuppressive Agents, Phosphorylation, Benzoquinones, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Mice, Knockout, COS Cells, Sirolimus, Lafora Disease, RNA Interference, RNA, Small Interfering, Ubiquitin-Protein Ligases, Lactams, Macrocyclic, Glucose Transporter Type 1, Mice, Protein Tyrosine Phosphatases, Non-Receptor, Dual-Specificity Phosphatases, TOR Serine-Threonine Kinases

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