bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2022–07–03
eight papers selected by
  1. Modeling tuberous sclerosis complex with human induced pluripotent stem cells.
  2. Individualized everolimus treatment for tuberous sclerosis-related angiomyolipoma promotes treatment adherence and response.
  3. Epileptic spasms are associated with increased SEEG derived functional connectivity in tuberous sclerosis complex.
  4. Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine.
  5. Nordic treatment guidelines for rare epileptic conditions: A literature review.
  6. mTOR pathway mediates endoplasmic reticulum stress-induced CD4+ T cell apoptosis in septic mice.
  7. Molecular mechanism of S-adenosylmethionine sensing by SAMTOR in mTORC1 signaling.
  8. The mTORC1-SLC4A7 axis stimulates bicarbonate import to enhance de novo nucleotide synthesis.
  1. World J Pediatr. 2022 Jun 27.
    Modeling tuberous sclerosis complex with human induced pluripotent stem cells.
    Weibo Niu, Benjamin Siciliano, Zhexing Wen.
       BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with a birth incidence of 1:6000 in the United States that is characterized by the growth of non-cancerous tumors in multiple organ systems including the brain, kidneys, lungs, and skin. Importantly, TSC is also associated with significant neurological manifestations including epilepsy, TSC-associated neuropsychiatric disorders, intellectual disabilities, and autism spectrum disorder. Mutations in the TSC1 or TSC2 genes are well-established causes of TSC, which lead to TSC1/TSC2 deficiency in organs and hyper-activation of the mammalian target of rapamycin signaling pathway. Animal models have been widely used to study the effect of TSC1/2 genes on the development and function of the brain. Despite considerable progress in understanding the molecular mechanisms underlying TSC in animal models, a human-specific model is urgently needed to investigate the effects of TSC1/2 mutations that are unique to human neurodevelopment.
    DATA SOURCES: Literature reviews and research articles were published in PubMed-indexed journals.
    RESULTS: Human-induced pluripotent stem cells (iPSCs), which capture risk alleles that are identical to their donors and have the capacity to differentiate into virtually any cell type in the human body, pave the way for the empirical study of previously inaccessible biological systems such as the developing human brain.
    CONCLUSIONS: In this review, we present an overview of the recent progress in modeling TSC with human iPSC models, the existing limitations, and potential directions for future research.
    Keywords:  Induced pluripotent stem cells; Three-dimensional cultures; Tuberous sclerosis complex; Two-dimensional cultures
    DOI:  https://doi.org/10.1007/s12519-022-00576-8
  2. Clin Kidney J. 2022 Jun;15(6): 1160-1168
    Individualized everolimus treatment for tuberous sclerosis-related angiomyolipoma promotes treatment adherence and response.
    Noelle K X Chung, Peter Metherall, Janet A McCormick, Roslyn J Simms, Albert C M Ong.
       Background: Everolimus is a potential alternative to embolization and nephrectomy for managing tuberous sclerosis complex (TSC)-associated renal angiomyolipoma (AML). In 2016, National Health Service England approved its use through regional centres for renal AML ≥30 mm showing interval growth. Evidence of lesion stabilization or reduction after 6 months is mandated for continuation of long-term treatment.
    Methods: From November 2016 to June 2021, all potentially eligible adult TSC patients with AML across Yorkshire and Humber were referred for assessment and monitoring. Eligible patients underwent baseline renal magnetic resonance imaging (MRI) assessment and a follow-up MRI scan after 6 months on everolimus. Dose titration was guided by trough levels and lesion responsiveness using a new 3D MRI volumetric protocol.
    Results: Of 28 patients commencing treatment, 19 tolerated everolimus for >3 months. Overall, 11 patients (40%) discontinued treatment, mostly due to recurrent infections (42%) and allergic reactions (25%). Sixty-eight percent required dose adjustments from the initiating dose (10 mg) due to sub-optimal trough levels (38%), minimal AML response (15%) or adverse events (47%). 3D volumetric assessment confirmed a reduction in AML volume of a pre-selected index lesion in all treatment-naïve cases (n = 14), showing superiority over 2D measurements of lesion diameter.
    Conclusion: In this cohort, everolimus promoted AML regression in all patients who tolerated the drug for >6 months with stabilization observed over 3 years. Trough levels enabled individual dose titration to maximize responsiveness and minimize side effects. The use of 3D MRI assessment of lesion volume was superior to 2D measurements of lesion diameter in monitoring treatment response.
    Keywords:  angiomyolipoma; everolimus; monitoring; safety; treatment outcome; tuberous sclerosis complex
    DOI:  https://doi.org/10.1093/ckj/sfac037
  3. Epilepsia. 2022 Jul 01.
    Epileptic spasms are associated with increased SEEG derived functional connectivity in tuberous sclerosis complex.
    Andrew Neal, Romain Bouet, Stanislas Lagarde, Karine Ostrowsky-Coste, Louis Maillard, Philippe Kahane, Renaud Touraine, Helene Catenoix, Alexandra Montavont, Jean Isnard, Alexis Arzimanoglou, Marc Hermier, Marc Guenot, Fabrice Bartolomei, Sylvain Rheims, Julien Jung.
       OBJECTIVE: Epileptic Spasms (ES) are common in Tuberous Sclerosis Complex (TSC). However the underlying network alterations and relationship with epileptogenic tubers are poorly understood. We examined interictal functional connectivity (FC) using stereo-EEG (SEEG) in patients with TSC to investigate the relationship between tubers, epileptogenicity and ES.
    METHODS: We analysed 18 patients with TSC who underwent SEEG (mean age 11.5 years). The dominant tuber (DT) was defined as the most epileptogenic tuber using the Epileptogenicity Index. Epileptogenic Zone (EZ) organisation was quantitatively separated into focal (isolated DT) and complex (all other patterns). Using a 20 minute interictal recording, FC was estimated with non-linear regression, h2 . We calculated i) intrazone FC within all sampled tubers and normal appearing cortical zones respectively, and ii) interzone FC involving connections between DT, other tubers and normal cortex. The relationship between FC and i) presence of ES as a current seizure type at the time of SEEG, ii) EZ organisation, iii) epileptogenicity was analysed using a mixed generalized linear model. Spike rate and distance between zones were considered in the model as covariates RESULTS: Six patients had ES as a current seizure type at time of SEEG. ES patients had a great number of tubers with FLAIR hypointense centre (p < 0.001) and none had TSC1 mutations. The presence of ES was independently associated with increased FC within both intrazone (p = 0.033) and interzone (p = 0.011) networks. Post-hoc analyses identified that increased FC was associated with ES across tuber and non-tuber networks. EZ organisation and epileptogenicity biomarkers were not associated with FC.
    SIGNIFICANCE: Increased cortical synchrony amongst both tuber and non-tuber networks is characteristic of patients with ES and independent of both EZ organisation and tuber epileptogenicity. This further supports the prospect of FC biomarkers aiding treatment paradigms in TSC.
    Keywords:  Stereo-EEG; epileptogenicity; network; tubers
    DOI:  https://doi.org/10.1111/epi.17353
  4. Science. 2022 Jul;377(6601): 47-56
    Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine.
    Andrew L Cangelosi, Anna M Puszynska, Justin M Roberts, Andrea Armani, Thao P Nguyen, Jessica B Spinelli, Tenzin Kunchok, Brianna Wang, Sze Ham Chan, Caroline A Lewis, William C Comb, George W Bell, Aharon Helman, David M Sabatini.
      The mechanistic target of rapamycin complex 1 (mTORC1) kinase controls growth in response to nutrients, including the amino acid leucine. In cultured cells, mTORC1 senses leucine through the leucine-binding Sestrin proteins, but the physiological functions and distribution of Sestrin-mediated leucine sensing in mammals are unknown. We find that mice lacking Sestrin1 and Sestrin2 cannot inhibit mTORC1 upon dietary leucine deprivation and suffer a rapid loss of white adipose tissue (WAT) and muscle. The WAT loss is driven by aberrant mTORC1 activity and fibroblast growth factor 21 (FGF21) production in the liver. Sestrin expression in the liver lobule is zonated, accounting for zone-specific regulation of mTORC1 activity and FGF21 induction by leucine. These results establish the mammalian Sestrins as physiological leucine sensors and reveal a spatial organization to nutrient sensing by the mTORC1 pathway.
    DOI:  https://doi.org/10.1126/science.abi9547
  5. Brain Behav. 2022 Jun 28. e2622
    Nordic treatment guidelines for rare epileptic conditions: A literature review.
    Kishan Vyas, Hannah Luedke, Benjamin Ruban-Fell.
       INTRODUCTION: The onset of severe, drug-resistant seizures in early childhood is characteristic of the rare epileptic disorders Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and CDKL5 deficiency disorder (CDD) and is frequently observed in the rare genetic conditions tuberous sclerosis complex (TSC) and Rett syndrome (RTT). High-quality treatment guidelines are needed for optimal management of these conditions. This review aimed to assess content, availability, and development of treatment guidelines for these disorders in the Nordics region (Denmark, Finland, Iceland, Norway, and Sweden).
    METHODS: A targeted literature review (TLR) was therefore conducted in November/December 2020 by manually searching online rare disease and guideline databases in addition to relevant health technology assessment and regulatory agency websites to identify pharmacological treatment guidelines for DS, LGS, TSC, RTT, and CDD. Search terms for each disorder were translated to identify country-specific guidelines. Treatment recommendations, geographical focus, and guideline development methodology was extracted into a predetermined extraction grid.
    RESULTS: Most of the 24 eligible guidelines identified (16/24; 66%) were specific to particular countries; Sweden was the most represented (7/24 [29%] guidelines), while no guidelines were identified for Iceland. Guideline development methodologies were heterogeneous, including systematic literature reviews/TLRs and expert consultation; several methodologies did not report details on the evidence sources used (7/24 [29%] guidelines). Treatment recommendation availability was variable across disorders, ranging from 126 treatment recommendations (LGS) to none (RTT, CDD).
    CONCLUSION: Comprehensive, consensus-based treatment guidance developed via international collaboration within the Nordics region is necessary to optimize patient care in these five rare epileptic conditions.
    Keywords:  CDKL5 deficiency disorder; Lennox-Gastaut syndrome; Rett syndrome; myoclonic epilepsies; practice guidelines; tuberous sclerosis complex
    DOI:  https://doi.org/10.1002/brb3.2622
  6. Apoptosis. 2022 Jun 27.
    mTOR pathway mediates endoplasmic reticulum stress-induced CD4+ T cell apoptosis in septic mice.
    Guangxu Bai, Hao Wang, Na Cui.
      Endoplasmic reticulum stress (ERS) has been well documented to participate in the pathophysiological processes of apoptosis in many diseases. Inhibition of ERS ameliorates pathological organ injury. However, the upstream signaling pathways and molecular regulatory mechanisms of which are still unknown. mTOR, an evolutionarily conserved protein kinase, is a key regulator of apoptosis. Hence, in this study, a classical cecal ligation and puncture (CLP) sepsis model was constructed by using the T cell-specific knockout mTOR and TSC1 (Tuberous Sclerosis Complex, the inhibitor of mTOR signaling pathway) mice to explore the underlying signaling pathway and molecular mechanism of host immune imbalance caused by apoptosis in sepsis. We found that mTOR may modulate septic T cell apoptosis by regulating Akt-IRE1-JNK pathway. To further clarify the possible mechanism, the specific inhibitors of PI3K-Akt and IRE1-JNK were used to intervene in mice before/after CLP, respectively. By analyzing the proteins of mTOR-ERS signaling pathway and the expression of apoptosis-related proteins and genes, we found that mTOR mediated the ER stress induced CD4+ T cell apoptosis in Septic mice by negatively regulating the Akt-IRE1-JNK-Caspase 3 signaling cascades. These results indicate that mTOR-Akt-IRE1α-JNK signaling pathway mediated the Endoplasmic reticulum stress induced CD4+ T cell apoptosis in Septic mice.
    Keywords:  Apoptosis; CLP; Endoplasmic reticulum stress; IRE1–JNK; Mammalian target of rapamycin
    DOI:  https://doi.org/10.1007/s10495-022-01740-1
  7. Sci Adv. 2022 Jul;8(26): eabn3868
    Molecular mechanism of S-adenosylmethionine sensing by SAMTOR in mTORC1 signaling.
    Xin Tang, Yifan Zhang, Guanchao Wang, Chunxiao Zhang, Fang Wang, Jiawen Shi, Tianlong Zhang, Jianping Ding.
      The mechanistic target of rapamycin-mLST8-raptor complex (mTORC1) functions as a central regulator of cell growth and metabolism in response to changes in nutrient signals such as amino acids. SAMTOR is an S-adenosylmethionine (SAM) sensor, which regulates the mTORC1 activity through its interaction with the GTPase-activating protein activity toward Rags-1 (GATOR1)-KPTN, ITFG2, C12orf66 and SZT2-containing regulator (KICSTOR) complex. In this work, we report the crystal structures of Drosophila melanogaster SAMTOR in apo form and in complex with SAM. SAMTOR comprises an N-terminal helical domain and a C-terminal SAM-dependent methyltransferase (MTase) domain. The MTase domain contains the SAM-binding site and the potential GATOR1-KICSTOR-binding site. The helical domain functions as a molecular switch, which undergoes conformational change upon SAM binding and thereby modulates the interaction of SAMTOR with GATOR1-KICSTOR. The functional roles of the key residues and the helical domain are validated by functional assays. Our structural and functional data together reveal the molecular mechanism of the SAM sensing of SAMTOR and its functional role in mTORC1 signaling.
    DOI:  https://doi.org/10.1126/sciadv.abn3868
  8. Mol Cell. 2022 Jun 24. pii: S1097-2765(22)00544-5. [Epub ahead of print]
    The mTORC1-SLC4A7 axis stimulates bicarbonate import to enhance de novo nucleotide synthesis.
    Eunus S Ali, Anna Lipońska, Brendan P O'Hara, David R Amici, Michael D Torno, Peng Gao, John M Asara, Mee-Ngan F Yap, Marc L Mendillo, Issam Ben-Sahra.
      Bicarbonate (HCO3-) ions maintain pH homeostasis in eukaryotic cells and serve as a carbonyl donor to support cellular metabolism. However, whether the abundance of HCO3- is regulated or harnessed to promote cell growth is unknown. The mechanistic target of rapamycin complex 1 (mTORC1) adjusts cellular metabolism to support biomass production and cell growth. We find that mTORC1 stimulates the intracellular transport of HCO3- to promote nucleotide synthesis through the selective translational regulation of the sodium bicarbonate cotransporter SLC4A7. Downstream of mTORC1, SLC4A7 mRNA translation required the S6K-dependent phosphorylation of the translation factor eIF4B. In mTORC1-driven cells, loss of SLC4A7 resulted in reduced cell and tumor growth and decreased flux through de novo purine and pyrimidine synthesis in human cells and tumors without altering the intracellular pH. Thus, mTORC1 signaling, through the control of SLC4A7 expression, harnesses environmental bicarbonate to promote anabolic metabolism, cell biomass, and growth.
    Keywords:  SLC4A7/NBCn1; bicarbonate metabolism; mTOR signaling; purine metabolism; pyrimidine metabolism
    DOI:  https://doi.org/10.1016/j.molcel.2022.06.008
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