ArticleProceedings of the National Academy of Sciences of the United States of America2019
Abnormal glycogen storage in tuberous sclerosis complex caused by impairment of mTORC1-dependent and -independent signaling pathways.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 24 citations in OpenAlex.
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)Autophagy · 2021Guideline
- TSC2 is a stress granule suppressor.bioRxiv : the preprint server for biology · 2026Article
- mTOR signaling networks: mechanistic insights and translational frontiers in disease therapeutics.Signal transduction and targeted therapy · 2025Review
- Uncomplexed-TSC1 deploys novel mTORC1-independent pathway to exacerbate the liver glycogen storage in TSC.Cell death & disease · 2025Article
- Identify the origin of de novo variants in TSC patients by ddPCR.Acta epileptologica · 2025Article
- TSC complex decrease the expression of mTOR by regulated miR-199b-3p.Scientific reports · 2025Article
- Drug Treatments for Neurodevelopmental Disorders: Targeting Signaling Pathways and Homeostasis.Current neurology and neuroscience reports · 2024Review
- mTORC1 controls murine postprandial hepatic glycogen synthesis via Ppp1r3b.The Journal of clinical investigation · 2024Article
- Lysosomal glucose sensing and glycophagy in metabolism.Trends in endocrinology and metabolism: TEM · 2023Review
- Severe kidney dysfunction in sialidosis mice reveals an essential role for neuraminidase 1 in reabsorption.JCI insight · 2023Article
- Regulation and metabolic functions of mTORC1 and mTORC2.Physiological reviews · 2021Review
- CHIR99021 Augmented the Function of Late Endothelial Progenitor Cells by Preventing Replicative Senescence.International journal of molecular sciences · 2021Article
- Primary cells derived from Tuberous Sclerosis Complex patients show autophagy alteration in the haploinsufficiency state.Genetics and molecular biology · 2021Article
- Renal angiomyolipoma (AML) harboring a missense mutation ofCancer biology & therapy · 2020Article
- Survival prediction for patients with lung adenocarcinoma: A prognostic risk model based on gene mutations.Cancer biomarkers : section A of Disease markers · 2020Article
- mTOR and autophagy pathways are dysregulated in murine and human models of Schaaf-Yang syndrome.Scientific reports · 2019Article
- Review
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3 authors at 1 institution in 1 country.
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Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that causes tumor formation in multiple organs. TSC is caused by inactivating mutations in the genes encoding TSC1/2, negative regulators of the mammalian target of rapamycin complex 1 (mTORC1). Diminished TSC function is associated with excess glycogen storage, but the causative mechanism is unknown. By studying human and mouse cells with defective or absent TSC2, we show that complete loss of TSC2 causes an increase in glycogen synthesis through mTORC1 hyperactivation and subsequent inactivation of glycogen synthase kinase 3β (GSK3β), a negative regulator of glycogen synthesis. Specific TSC2 pathogenic mutations, however, result in elevated glycogen levels with no changes in mTORC1 or GSK3β activities. We identify mTORC1-independent lysosomal depletion and impairment of autophagy as the driving causes underlying abnormal glycogen storage in TSC irrespective of the underlying mutation. The defective autophagic degradation of glycogen is associated with abnormal ubiquitination and degradation of essential proteins of the autophagy-lysosome pathway, such as LC3 and lysosomal associated membrane protein 1 and 2 (LAMP1/2) and is restored by the combined use of mTORC1 and Akt pharmacological inhibitors. In complementation to current models that place mTORC1 as the central therapeutic target for TSC pathogenesis, our findings identify mTORC1-independent pathways that are dysregulated in TSC and that should therefore be taken into account in the development of a therapeutic treatment.
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