bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2021‒03‒07
twelve papers selected by
Marti Cadena Sandoval

  1. Front Neurol. 2021 ;12 639319
      Epilepsy affects ~5 out of every 10,000 children per year. Up to one-third of these children have medically refractory epilepsy, with limited to no options for improved seizure control. mTOR, a ubiquitous 289 kDa serine/threonine kinase in the phosphatidylinositol 3-kinase (PI3K)-related kinases (PIKK) family, is dysregulated in a number of human diseases, including tuberous sclerosis complex (TSC) and epilepsy. In cell models of epilepsy and TSC, rapamycin, an mTOR inhibitor, has been shown to decrease seizure frequency and duration, and positively affect cell growth and morphology. Rapamycin has also been shown to prevent or improve epilepsy and prolong survival in animal models of TSC. To date, clinical studies looking at the effects of mTOR inhibitors on the reduction of seizures have mainly focused on patients with TSC. Everolimus (Novartis Pharmaceuticals), a chemically modified rapamycin derivative, has been shown to reduce seizure frequency with reasonable safety and tolerability. Mutations in mTOR or the mTOR pathway have been found in hemimegalencephaly (HME) and focal cortical dysplasias (FCDs), both of which are highly correlated with medically refractory epilepsy. Given the evidence to date, a logical next step is to investigate the role of mTOR inhibitors in the treatment of children with medically refractory non-TSC epilepsy, particularly those children who have also failed resective surgery.
    Keywords:  cortical dysplasia; hemimegalencephaly; mTOR; non-tuberous sclerosis complex-related epilepsy; pediatric epilepsy
  2. Epilepsy Res. 2021 Feb 08. pii: S0920-1211(21)00025-5. [Epub ahead of print]171 106572
      Our previous studies suggest the tuber center is the seizure focus in tuberous sclerosis complex (TSC). We report findings from 5 epilepsy surgeries in 4 children with TSC and focal motor seizures from single tubers in primary sensorimotor cortex in which resection was limited to the cortex in the tuber center. Intraoperative electrocorticography showed epileptiform activity in the tuber center, with or without propagation to the tuber rim and surrounding perituberal cortex. Histopathology showed an abundance of dysmorphic neurons in the tuber center compared to the rim in four paired specimens, dysmorphic neurons being the reported epileptogenic cell line in TSC. Associated focal motor seizures were eliminated in all children (mean follow up 6.3 years) without postoperative deficits. Tuber center resections are a potential alternative to complete tuberectomy in patients with epileptogenic tubers in eloquent cortex and potentially also in children with a high tuber load and multifocal seizures.
    Keywords:  Cortical dysplasia; Dysmorphic neurons; Electrocorticography; Epilepsy; Epilepsy surgery
  3. Am J Med Genet A. 2021 Mar 01.
      Sleep disorders are frequent in tuberous sclerosis complex (TSC) during the developmental age but are not well characterized. Forty-six TSC patients and 46 healthy age- and sex-matched controls were enrolled. Their parents completed the Sleep Disturbances Scale for Children (SDSC) and the Child Behavior Checklist (CBCL). A total of 17.4% of the TSC patients obtained a total pathologic score at the SDSC versus 4.4% in the control group (p = 0.024). 45.7% of individuals with TSC reported a pathologic score in at least one of the factors. We found a statistically significant difference between the TSC cohort and healthy controls for most of the CBCL scales scores. A significant relationship was found between the Total SDSC score and the Total CBCL score (R-square = 0.387, p < 0.0001), between the Total SDSC score and the Internalizing and Externalizing areas scores (R-square = 0.291, p < 0.0001 and R-square = 0.350, p < 0.0001, respectively) of the CBCL. Sleep disorders are more frequent in TSC than in the general population and correlate with behavior. The use of SDSC and CBCL is proposed as part of the surveillance of TSC patients in the developmental age.
    Keywords:  CBCL; SDSC; TSC; sleep; tuberous sclerosis complex
  4. Cardiol Young. 2021 Mar 04. 1-4
      Tuberous sclerosis complex is a rare multisystem genetic disorder characterised by the growth of numerous tumour-like malformations in many parts of the body including skin, kidneys, brain, lung, eyes, liver, and heart. Mutations in the TSC1 or TSC2 genes have been reported to cause disruption in the TSC1-TSC2 intracellular protein complex, causing over-activation of the mammalian target of rapamycin protein complex. In this study, we present a 3-month-old male infant diagnosed with tuberous sclerosis, bilateral neurosensorial hearing loss, Wolff-Parkinson-White syndrome on electrocardiography, multiple cardiac rhabdomyomas with severe stenosis in the left ventricular outflow tract, who responded well to the Everolimus therapy.
    Keywords:  Cardiac rhabdomyoma; Everolimus; Wolff–Parkinson–White syndrome; hearing loss; tuberous sclerosis
  5. J Pediatr. 2021 Feb 25. pii: S0022-3476(21)00199-2. [Epub ahead of print]
      OBJECTIVE: To correlate fetal brain MRI findings with epilepsy characteristics and neurodevelopment at two years of age in children with Tuberous Sclerosis Complex (TSC) in order to improve prenatal counseling STUDY DESIGN: This retrospective cohort study was performed in a collaboration between centers of the EPISTOP consortium. We included children with definite TSC, fetal MRIs, and available follow-up data at two years of age. A pediatric neuroradiologist masked to the patient´s clinical characteristics evaluated all fetal MRIs. MRIs were categorized for each of the ten brain lobes as score 0: no (sub)cortical lesions or doubt; score 1: a single small lesion; score 2: more than one small lesion or at least one large lesion (> 5mm). Neurological manifestations were correlated to lesion sum scores RESULTS: Forty-one children were included. Median gestational age at MRI was 33.3 weeks; (sub)cortical lesions were detected in 97.6%. Mean lesion sum score was 4.5. At two years, 58.5% of patients had epilepsy and 22% had drug-resistant epilepsy. Cognitive, language, and motor development were delayed in 38%, 81%, and 50% of patients, respectively. Autism spectrum disorder (ASD) was diagnosed in 20.5%. Fetal MRI lesion sum scores were significantly associated with cognitive and motor development, and with ASD diagnosis, but not with epilepsy characteristics CONCLUSION: Fetal cerebral lesion scores correlate with neurodevelopment and ASD at two years in children with TSC.
    Keywords:  TSC; development; epilepsy; imaging; prenatal
  6. Int J Mol Sci. 2021 Feb 24. pii: 2233. [Epub ahead of print]22(5):
      The mechanistic target of rapamycin (mTOR) and wingless-related integration site (Wnt) signal transduction networks are evolutionarily conserved mammalian growth and cellular development networks. Most cells express many of the proteins in both pathways, and this review will briefly describe only the key proteins and their intra- and extracellular crosstalk. These complex interactions will be discussed in relation to cancer development, drug resistance, and stem cell exhaustion. This review will also highlight the tumor-suppressive tuberous sclerosis complex (TSC) mutated, mTOR-hyperactive lung disease of women, lymphangioleiomyomatosis (LAM). We will summarize recent advances in the targeting of these pathways by monotherapy or combination therapy, as well as future potential treatments.
    Keywords:  GSK3β; TSC1/2; Wnt/β-catenin; cancer; lymphangioleiomyomatosis; mTOR
  7. Proc Natl Acad Sci U S A. 2021 Mar 09. pii: e2021945118. [Epub ahead of print]118(10):
      Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a central regulator of cell growth and metabolism that senses and integrates nutritional and environmental cues with cellular responses. Recent studies have revealed critical roles of mTORC1 in RNA biogenesis and processing. Here, we find that the m6A methyltransferase complex (MTC) is a downstream effector of mTORC1 during autophagy in Drosophila and human cells. Furthermore, we show that the Chaperonin Containing Tailless complex polypeptide 1 (CCT) complex, which facilitates protein folding, acts as a link between mTORC1 and MTC. The mTORC1 activates the chaperonin CCT complex to stabilize MTC, thereby increasing m6A levels on the messenger RNAs encoding autophagy-related genes, leading to their degradation and suppression of autophagy. Altogether, our study reveals an evolutionarily conserved mechanism linking mTORC1 signaling with m6A RNA methylation and demonstrates their roles in suppressing autophagy.
    Keywords:  autophagy; chaperonin containing Tailless complex polypeptide 1 (CCT); m6A RNA methylation; m6A methyltransferase complex (MTC); mTORC1
  8. Elife. 2021 Mar 01. pii: e63326. [Epub ahead of print]10
      The mechanistic target of rapamycin complex 1 (mTORC1) stimulates a coordinated anabolic program in response to growth-promoting signals. Paradoxically, recent studies indicate that mTORC1 can activate the transcription factor ATF4 through mechanisms distinct from its canonical induction by the integrated stress response (ISR). However, its broader roles as a downstream target of mTORC1 are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon insulin-stimulated mTORC1 signaling to those activated by the ISR. In multiple mouse embryo fibroblast (MEF) and human cancer cell lines, the mTORC1-ATF4 pathway stimulated expression of only a subset of the ATF4 target genes induced by the ISR, including genes involved in amino acid uptake, synthesis, and tRNA charging. We demonstrate that ATF4 is a metabolic effector of mTORC1 involved in both its established role in promoting protein synthesis and in a previously unappreciated function for mTORC1 in stimulating cellular cystine uptake and glutathione synthesis.
    Keywords:  cancer biology; cell biology; human; mouse; rat
  9. Pediatr Neurol. 2020 Dec 26. pii: S0887-8994(20)30393-3. [Epub ahead of print]117 21-26
      BACKGROUND: Kidney disease has historically been the primary source of early mortality in adults with tuberous sclerosis complex (TSC). Kidney imaging surveillance promotes early detection of lesions requiring intervention. We describe kidney imaging frequency in relationship to patient-level characteristics for commercially insured patients with TSC in the United States.METHODS: This retrospective observational study used 2003 to 2016 enrollment and claims data from a de-identified fully insured commercial health insurer. Patients with TSC less than 65 years were included. The patient-level kidney imaging rate was calculated as the number of kidney imaging procedures divided by length of continuous enrollment. A multiple linear regression model was used to determine the relationship between imaging rate and progression of TSC-associated kidney disease, number of specialists seen, and nephrologist care.
    RESULTS: At least half of the 70 patients with TSC included in the study were aged 16 years or younger. Over a follow-up period of up to 14 years, the median kidney imaging rate was 0.13 procedures per year with 43% (N = 30) of patients lacking evidence of kidney imaging during the observation period. Imaging frequency increased with progression of TSC-associated kidney disease, more specialists, and nephrologist care (P < 0.05 for all three in regression model).
    CONCLUSIONS: A substantial percentage of patients with TSC in the United States are at risk for delayed detection of kidney manifestations due to infrequent kidney imaging surveillance. Multispecialty care, including neurologists, may positively affect kidney surveillance rates.
    Keywords:  Angiomyolipoma; Claims data; Imaging; Kidney; Surveillance; Tuberous sclerosis complex
  10. Neurochem Res. 2021 Mar 04.
      Changes in astrocyte channels, transporters, and metabolism play a critical role in seizure generation and epilepsy. In particular, alterations in astrocyte potassium, glutamate, water and adenosine homeostasis and gap junctional coupling have all been associated with hyperexcitability and epileptogenesis (largely in temporal lobe epilepsy). Distinct astrocytic changes have also been identified in other types of epilepsy, such as tuberous sclerosis, tumor-associated epilepsy and post-traumatic epilepsy. Together, the emerging literature on astrocytes and epilepsy provides powerful rationale for distinct new therapeutic targets that are astrocyte-specific.
    Keywords:  Adenosine; Astrocyte; Epilepsy; Gap junction; Glutamate; Potassium
  11. Int J Mol Sci. 2021 Feb 11. pii: 1784. [Epub ahead of print]22(4):
      The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth, proliferation, and metabolism by integrating various environmental inputs including growth factors, nutrients, and energy, among others. mTOR signaling has been demonstrated to control almost all fundamental cellular processes, such as nucleotide, protein and lipid synthesis, autophagy, and apoptosis. Over the past fifteen years, mapping the network of the mTOR pathway has dramatically advanced our understanding of its upstream and downstream signaling. Dysregulation of the mTOR pathway is frequently associated with a variety of human diseases, such as cancers, metabolic diseases, and cardiovascular and neurodegenerative disorders. Besides genetic alterations, aberrancies in post-translational modifications (PTMs) of the mTOR components are the major causes of the aberrant mTOR signaling in a number of pathologies. In this review, we summarize current understanding of PTMs-mediated regulation of mTOR signaling, and also update the progress on targeting the mTOR pathway and PTM-related enzymes for treatment of human diseases.
    Keywords:  human diseases; inhibitors; mTOR; post-translational modifications
  12. Int J Mol Sci. 2021 Feb 21. pii: 2144. [Epub ahead of print]22(4):
      Pulmonary arterial hypertension (PAH) is a progressive and fatal disease without a cure. The exact pathogenic mechanisms of PAH are complex and poorly understood, yet a number of abnormally expressed genes and regulatory pathways contribute to sustained vasoconstriction and vascular remodeling of the distal pulmonary arteries. Mammalian target of rapamycin (mTOR) is one of the major signaling pathways implicated in regulating cell proliferation, migration, differentiation, and protein synthesis. Here we will describe the canonical mTOR pathway, structural and functional differences between mTOR complexes 1 and 2, as well as the crosstalk with other important signaling cascades in the development of PAH. The pathogenic role of mTOR in pulmonary vascular remodeling and sustained vasoconstriction due to its contribution to proliferation, migration, phenotypic transition, and gene regulation in pulmonary artery smooth muscle and endothelial cells will be discussed. Despite the progress in our elucidation of the etiology and pathogenesis of PAH over the two last decades, there is a lack of effective therapeutic agents to treat PAH patients representing a significant unmet clinical need. In this review, we will explore the possibility and therapeutic potential to use inhibitors of mTOR signaling cascade to treat PAH.
    Keywords:  EndMT; RTK/PI3K/AKT/mTOR pathway; Raptor; Rictor; SMC transition