bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2022–04–10
eight papers selected by
  1. Independent temporal lobe epilepsy in patients with tuberous sclerosis complex.
  2. Current role of surgery for tuberous sclerosis complex-associated epilepsy.
  3. Perinatal adversities in tuberous sclerosis complex: determinants and neurodevelopmental outcomes.
  4. Commentary on "The epileptogenic zone in children with tuberous sclerosis complex is characterized by prominent features of focal cortical dysplasia".
  5. Opposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function.
  6. In Situ Analysis of mTORC1/C2 and Metabolism-Related Proteins in Pediatric Osteosarcoma.
  7. Targeting mTOR in the context of diet and whole-body metabolism.
  8. mTOR Signaling in Kidney Diseases.
  1. Pediatr Investig. 2022 Mar;6(1): 23-28
    Independent temporal lobe epilepsy in patients with tuberous sclerosis complex.
    Tinghong Liu, Jing Ding, Shaohui Zhang, Yangshuo Wang, Jinshan Xu, Liu Yuan, Feng Zhai, Guojun Zhang, Shuli Liang.
      Tuberous sclerosis complex (TSC) is a rare disease that involves multiple organs, including the brain; approximately 80%-90% of TSC patients exhibit TSC-associated epilepsy. Independent temporal lobe epilepsy (TLE), TSC-unrelated epilepsy, is particularly rare in patients with TSC. Here, we describe three patients with TSC with independent TLEs that were confirmed by stereo-electroencephalography (EEG), postoperative pathological findings, and seizure outcome at follow-up. The patients were retrospectively enrolled at two centers; their ictal epileptiform discharge onsets were determined using electrode contacts in the hippocampus during stereo-EEG. The three patients underwent anterior temporal lobectomies and remained seizure-free at 1-5 years after surgery. Postoperative pathological examinations confirmed hippocampal sclerosis in all three patients. Furthermore, postoperative intelligence quotient improvement was evident in one patient, while the quality of life was improved in two patients at 12 months after surgery.
    Keywords:  Anterior temporal lobectomy; Hippocampal sclerosis; Temporal lobe epilepsy; Tuberous sclerosis complex
    DOI:  https://doi.org/10.1002/ped4.12315
  2. Pediatr Investig. 2022 Mar;6(1): 16-22
    Current role of surgery for tuberous sclerosis complex-associated epilepsy.
    Nicola Specchio, Giusy Carfi Pavia, Luca de Palma, Alessandro De Benedictis, Chiara Pepi, Marta Conti, Carlo Efisio Marras, Federico Vigevano, Paolo Curatolo.
      Tuberous sclerosis complex (TSC) is a rare multisystem, autosomal dominant neurocutaneous syndrome in which epilepsy is the most common of several neurological and psychiatric manifestations. Around two thirds of patients develop drug-resistant epilepsy for whom surgical resection of epileptogenic foci is indicated when seizures remain inadequately controlled following trial of two antiseizure medications. The challenge with presurgical and surgical approaches with patients with TSC is overcoming the complexity from the number of tubers and the multiplex epileptogenic network forming the epileptogenic zone. Data suggest that seizure freedom is achieved by 55%-60% of patients, but predictive factors for success have remained elusive, which makes for unconfident selection of surgical candidates. This article presents three different cases as illustrations of the potential challenges faced when assessing the suitability of TSC patients for epilepsy surgery.
    Keywords:  Epilepsy; Everolimus; Imaging; Prognostics; Surgery; Tuberous sclerosis complex (TSC)
    DOI:  https://doi.org/10.1002/ped4.12312
  3. Dev Med Child Neurol. 2022 Apr 02.
    Perinatal adversities in tuberous sclerosis complex: determinants and neurodevelopmental outcomes.
    Tuberous Sclerosis 2000 Study Group
       AIM: To examine the association between perinatal adversities and neurodevelopmental outcome in tuberous sclerosis complex (TSC).
    METHOD: The Tuberous Sclerosis 2000 study is a prospective, longitudinal UK study of TSC. In phase 1, mutation type, TSC family history, tuber characteristics, presence of cardiac rhabdomyomas, seizure characteristics, and intellectual ability were assessed in 125 children affected with TSC (64 females, 61 males; median age 39mo, range 4-254). In phase 2, 88 participants (49 females, 39 males; median age 148mo, range 93-323) were assessed for neurodevelopmental outcomes including intellectual ability, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Perinatal histories of 88 participants with TSC and 80 unaffected siblings were collected retrospectively using the Obstetric Enquiry Schedule and coded with a modified Gillberg Optimality Scale to measure levels of perinatal adversity. Data were analysed using Mann-Whitney U tests, Spearman's rank correlation, and linear regression with robust standard errors.
    RESULTS: Children with familial TSC experienced significantly greater perinatal adversity than unaffected siblings. Perinatal adversity was higher in children with TSC-affected mothers than those with unaffected mothers. There was no significant association between perinatal adversities and neurodevelopmental outcomes after controlling for confounders.
    INTERPRETATION: Maternal TSC is a significant marker of elevated perinatal risk in addition to risks incurred by fetal genotype. Pregnancies complicated by maternal or fetal TSC require higher vigilance, and mechanisms underlying increased perinatal adversity require further research.
    DOI:  https://doi.org/10.1111/dmcn.15224
  4. Epilepsia Open. 2022 Apr 04.
    Commentary on "The epileptogenic zone in children with tuberous sclerosis complex is characterized by prominent features of focal cortical dysplasia".
    Michael Wong.
      
    DOI:  https://doi.org/10.1002/epi4.12598
  5. Nat Commun. 2022 Apr 04. 13(1): 1783
    Opposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function.
    Liad Hinden, Majdoleen Ahmad, Sharleen Hamad, Alina Nemirovski, Gergő Szanda, Sandra Glasmacher, Aviram Kogot-Levin, Rinat Abramovitch, Bernard Thorens, Jürg Gertsch, Gil Leibowitz, Joseph Tam.
      Activation of the cannabinoid-1 receptor (CB1R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of diabetic kidney disease (DKD). However, the CB1R/mTORC1 signaling axis in the kidney has not been described yet. We show here that hyperglycemia-induced endocannabinoid/CB1R stimulation increased mTORC1 activity, enhancing the transcription of the facilitative glucose transporter 2 (GLUT2) and leading to the development of DKD in mice; this effect was ameliorated by specific RPTCs ablation of GLUT2. Conversely, CB1R maintained the normal activity of mTORC1 by preventing the cellular excess of amino acids during normoglycemia. Our findings highlight a novel molecular mechanism by which the activation of mTORC1 in RPTCs is tightly controlled by CB1R, either by enhancing the reabsorption of glucose and inducing kidney dysfunction in diabetes or by preventing amino acid uptake and maintaining normal kidney function in healthy conditions.
    DOI:  https://doi.org/10.1038/s41467-022-29124-8
  6. Pathol Oncol Res. 2022 ;28 1610231
    In Situ Analysis of mTORC1/C2 and Metabolism-Related Proteins in Pediatric Osteosarcoma.
    Anna Mohás, Ildikó Krencz, Zsófia Váradi, Gabriella Arató, Luca Felkai, Dorottya Judit Kiss, Dorottya Moldvai, Anna Sebestyén, Monika Csóka.
      Activation of the mTOR pathway has been observed in osteosarcoma, however the inhibition of mammalian target of rapamycin (mTOR) complex 1 has had limited results in osteosarcoma treatment. Certain metabolic pathways can be altered by mTOR activation, which can affect survival. Our aim was to characterize the mTOR profile and certain metabolic alterations in pediatric osteosarcoma to determine the interactions between the mTOR pathway and metabolic pathways. We performed immunohistochemistry on 28 samples to analyze the expression of mTOR complexes such as phospho-mTOR (pmTOR), phosphorylated ribosomal S6 (pS6), and rapamycin-insensitive companion of mTOR (rictor). To characterize metabolic pathway markers, we investigated the expression of phosphofructokinase (PFK), lactate dehydrogenase-A (LDHA), β-F1-ATPase (ATPB), glucose-6-phosphate dehydrogenase (G6PDH), glutaminase (GLS), fatty acid synthetase (FASN), and carnitin-O-palmitoyltransferase-1 (CPT1A). In total, 61% of the cases showed low mTOR activity, but higher pmTOR expression was associated with poor histological response to chemotherapy and osteoblastic subtype. Rictor expression was higher in metastatic disease and older age at the time of diagnosis. Our findings suggest the importance of the Warburg-effect, pentose-phosphate pathway, glutamine demand, and fatty-acid beta oxidation in osteosarcoma cells. mTOR activation is linked to several metabolic pathways. We suggest performing a detailed investigation of the mTOR profile before considering mTORC1 inhibitor therapy. Our findings highlight that targeting certain metabolic pathways could be an alternative therapeutic approach.
    Keywords:  mTOR; metabolic; metabolic adaptation; osteosarcoma; pathways; pediatric
    DOI:  https://doi.org/10.3389/pore.2022.1610231
  7. Endocrinology. 2022 Apr 02. pii: bqac041. [Epub ahead of print]
    Targeting mTOR in the context of diet and whole-body metabolism.
    Nikos Koundouros, John Blenis.
      The mechanistic target of rapamycin (mTOR) signaling pathway is the central regulator of cell growth and proliferation by integrating growth factor and nutrient availability. Under healthy physiological conditions, this process is tightly coordinated and essential to maintain whole-body homeostasis. Not surprisingly, dysregulated mTOR signaling underpins several diseases with increasing incidence worldwide, including obesity, diabetes and cancer. Consequently, there is significant clinical interest in developing therapeutic strategies that effectively target this pathway. The transition of mTOR inhibitors from the bench to bedside, however, has largely been marked with challenges and shortcomings, such as the development of therapy resistance and adverse side effects in patients. In this review, we discuss the current status of first, second and third generation mTOR inhibitors as a cancer therapy in both pre-clinical and clinical settings, with a particular emphasis on the mechanisms of drug resistance. We focus especially on the emerging role of diet as an important environmental determinant of therapy response, and posit a conceptual framework that links nutrient availability and whole-body metabolic states such as obesity with many of the previously defined processes that drive resistance to mTOR-targeted therapies. Given the role of mTOR as a central integrator of cell metabolism and function, we propose that modulating nutrient inputs through dietary interventions may influence the signaling dynamics of this pathway and compensatory nodes. In doing so, new opportunities for exploiting diet/drug synergies are highlighted that may unlock the therapeutic potential of mTOR inhibitors as a cancer treatment.
    Keywords:  diet; drug resistance; mTOR; metabolism
    DOI:  https://doi.org/10.1210/endocr/bqac041
  8. Kidney360. 2020 Nov 25. 1(11): 1319-1327
    mTOR Signaling in Kidney Diseases.
    Yuan Gui, Chunsun Dai.
      The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, is crucial in regulating cell growth, metabolism, proliferation, and survival. Under physiologic conditions, mTOR signaling maintains podocyte and tubular cell homeostasis. In AKI, activation of mTOR signaling in tubular cells and interstitial fibroblasts promotes renal regeneration and repair. However, constitutive activation of mTOR signaling in kidneys results in the initiation and progression of glomerular hypertrophy, interstitial fibrosis, polycystic kidney disease, and renal cell carcinoma. Here, we summarize the recent studies about mTOR signaling in renal physiology and injury, and discuss the possibility of its use as a therapeutic target for kidney diseases.
    Keywords:  TOR serine-threonine kinases; acute kidney injury; acute kidney injury and ICU nephrology; glomerular hypertrophy; kidney fibrosis; mTOR; polycystic kidney disease; renal cell carcinoma
    DOI:  https://doi.org/10.34067/KID.0003782020
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