bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2022–05–29
thirteen papers selected by
  1. Tuberous sclerosis complex-associated nonfunctional pancreatic neuroendocrine tumors: Management and surgical outcomes.
  2. Multiple folliculocystic and collagen hamartomas in a patient with tuberous sclerosis complex.
  3. Describing autism spectrum disorder in tuberous sclerosis complex: Challenges and future opportunities.
  4. Prenatal diagnosis and intervention improve developmental outcomes and epilepsy prognosis in children with tuberous sclerosis complex.
  5. Safety of inactivated COVID-19 vaccine in tuberous sclerosis complex patients with epilepsy treated with rapamycin.
  6. Epilepsy associated tuberous sclerosis; a case report from Bangladesh.
  7. The non-canonical nuclear functions of key players of the PI3K-AKT-MTOR pathway.
  8. Single Gene Mutations in Pkd1 or Tsc2 Alter Extracellular Vesicle Production and Trafficking.
  9. Rapid regression everolimus therapy in a neonate with cardiac rhabdomyoma.
  10. Amino acids control blood glucose levels through mTOR signaling.
  11. Spatiotemporal feedforward between PKM2 tetramers and mTORC1 prompts mTORC1 activation.
  12. Increased glycine contributes to synaptic dysfunction and early mortality in Nprl2 seizure model.
  13. Impact of Raptor and Rictor Deletion on Hippocampal Pathology Following Status Epilepticus.
  1. Am J Med Genet A. 2022 May 25.
    Tuberous sclerosis complex-associated nonfunctional pancreatic neuroendocrine tumors: Management and surgical outcomes.
    Leah M Evans, Kennedy R Geenen, Aileen O'Shea, Sandeep S Hedgire, Cristina R Ferrone, Elizabeth A Thiele.
      We aimed to further characterize pancreatic involvement in tuberous sclerosis complex (TSC), with a focus on management of TSC-associated nonfunctional pancreatic neuroendocrine tumors (PNETs). This was a retrospective chart review of a large cohort of TSC patients. A total of 637 patients with a confirmed diagnosis of TSC were seen at the Herscot Center for Tuberous Sclerosis Complex at Massachusetts General Hospital. Of the 637 total patients with a confirmed diagnosis of TSC, 28 patients were found to have varying pancreatic findings ranging from simple-appearing cysts to well-differentiated PNETs. Thirteen of the 28 patients had PNET confirmed on pathology; 10 of these tumors were resected at Massachusetts General Hospital. None of the patients had serious perioperative or postoperative complications; only one of the patients had a recurrence following resection. As roughly 4.4% of our TSC patient population had pancreatic involvement, surveillance abdominal imaging should include evaluation of the pancreas instead of limiting to a renal protocol. Additionally, given the low risk of complications and recurrence combined with documented risk of metastasis in TSC-associated PNET, TSC patients with pancreatic lesions suspicious for PNETs should be considered as surgical candidates.
    Keywords:  laparoscopy; mTOR inhibitor; pancreatic cyst; pancreatic neuroendocrine tumor; surgical intervention; tuberous sclerosis complex
    DOI:  https://doi.org/10.1002/ajmg.a.62850
  2. Actas Dermosifiliogr. 2022 May 24. pii: S0001-7310(22)00295-2. [Epub ahead of print]
    Multiple folliculocystic and collagen hamartomas in a patient with tuberous sclerosis complex.
    A Giacaman, C Saus Sarrias, G González López, A Martín-Santiago.
      
    DOI:  https://doi.org/10.1016/j.ad.2021.02.028
  3. Dev Med Child Neurol. 2022 May 28.
    Describing autism spectrum disorder in tuberous sclerosis complex: Challenges and future opportunities.
    Jamie K Capal.
      
    DOI:  https://doi.org/10.1111/dmcn.15296
  4. Dev Med Child Neurol. 2022 May 25.
    Prenatal diagnosis and intervention improve developmental outcomes and epilepsy prognosis in children with tuberous sclerosis complex.
    Xia Wang, Yifeng Ding, Yuanfeng Zhou, Lifei Yu, Shuizhen Zhou, Yi Wang, Ji Wang.
       AIM: To assess whether prenatal diagnosis and early intervention are beneficial for developmental outcomes and epilepsy prognosis in individuals with tuberous sclerosis complex (TSC).
    METHOD: This retrospective study originated from a single-centre TSC-specific cohort. We enrolled 273 individuals (138 males, 145 females; 2 years-7 years 6 months, mean 4 years 5 months, SD 1 year 6 months) with definitive TSC who completed TSC1/TSC2 genetic testing and were followed up to 2 years of age. The benefits of early attention and intervention were assessed by comparing epilepsy and developmental outcomes between groups with or without a prenatal diagnosis and with or without presymptomatic preventive intervention.
    RESULTS: The epilepsy occurrence rate was significantly lower in individuals diagnosed prenatally than in individuals diagnosed postnatally (p = 0.027). In individuals diagnosed prenatally, the epilepsy rate in the preventive intervention subgroup was significantly lower than that in the subgroup without preventive intervention (p = 0.008). Significant improvements in cognitive, language, and motor development were observed in individuals diagnosed prenatally compared to individuals diagnosed postnatally and in the preventive intervention subgroup compared to the subgroup without preventive intervention (p < 0.05).
    INTERPRETATION: Based on this study, we cautiously speculate that early postpartum intervention may reduce the incidence of epilepsy and intractable epilepsy and improve developmental outcomes. Prophylactic intervention with sirolimus and vigabatrin may reduce the incidence of epilepsy. Larger prospective randomized controlled studies are required to support these findings.
    DOI:  https://doi.org/10.1111/dmcn.15265
  5. Seizure. 2022 May 16. pii: S1059-1311(22)00114-5. [Epub ahead of print]99 71-74
    Safety of inactivated COVID-19 vaccine in tuberous sclerosis complex patients with epilepsy treated with rapamycin.
    Qian Lu, Yang-Yang Wang, Qiu-Hong Wang, Li-Na Tang, Xiao-Yan Yang, Shuo Dun, Li-Ping Zou.
       PURPOSE: To assess the safety of inactivated coronavirus 2019 disease (COVID-19) vaccine in tuberous sclerosis complex (TSC) patients with epilepsy.
    METHODS: All patients with epilepsy were selected from Efficacy and Safety of Sirolimus in Pediatric Patients with Tuberous Sclerosis (ESOSPIT) project and younger than 17 years old. The patients were treated with mTOR inhibitors (rapamycin). A total of 44 patients who completed the two-dose inactivated COVID-19 vaccine between July 7, 2021, and January 1, 2022, were enrolled.
    RESULTS: The median age of seizure onset was 23 months. About two-thirds of patients have focal seizures. Thirty-three patients use antiseizure medications. The mean duration of rapamycin treatment was 55.59 ± 18.42 months. Adverse reactions within 28 days after injection occurred in 11 patients (25%), all were under 12 years old. Injection site pain was the most reported event (20.45%), which was mild in severity and improved within one day. All patients had no seizure-related changes after vaccination.
    CONCLUSION: This study shows that the inactivated COVID-19 vaccine was well tolerated and safe in TSC patients with epilepsy, as well as for those treated with mTOR inhibitors.
    Keywords:  COVID-19 vaccine; Epilepsy; Rapamycin; Tuberous sclerosis complex; mTOR inhibitor
    DOI:  https://doi.org/10.1016/j.seizure.2022.05.010
  6. Ann Med Surg (Lond). 2022 Jun;78 103738
    Epilepsy associated tuberous sclerosis; a case report from Bangladesh.
    Abhigan Babu Shrestha, Sajina Shrestha, Senjuti Seemanta, Pashupati Pokharel, Waqar Alam.
      Tuberous sclerosis or Bourneville's disease is a rare autosomal dominant disease affecting many organs like the brain, heart, lungs, eyes, kidneys and skin. It is characterized by neurological manifestation like epilepsy, cutaneous changes and the formation of benign lesions in multiple organs. The symptoms are apparent only in late childhood, which limits the early diagnosis in infancy. Here, we report a case of a 15 year old female child with tuberous sclerosis.
    Keywords:  Angiofibroma; Case report; Epilepsy; MRI; Subependymal nodules; Tuberous sclerosis complex
    DOI:  https://doi.org/10.1016/j.amsu.2022.103738
  7. J Cell Physiol. 2022 May 26.
    The non-canonical nuclear functions of key players of the PI3K-AKT-MTOR pathway.
    Sakshi Gupta, Mukund Kumar, Soumi Chaudhuri, Arun Kumar.
      The PI3K-AKT-MTOR signal transduction pathway is one of the essential signalling cascades within the cell due to its involvement in many vital functions. The pathway initiates with the recruitment of phosphatidylinositol-3 kinases (PI3Ks) onto the plasma membrane, generating phosphatidylinositol-3,4,5-triphosphate [PtdIns(3,4,5)P3 ] and subsequently activating AKT. Being the central node of the PI3K network, AKT activates the mechanistic target of rapamycin kinase complex 1 (MTORC1) via Tuberous sclerosis complex 2 inhibition in the cytoplasm. Although the cytoplasmic role of the pathway has been widely explored for decades, we now know that most of the effector molecules of the PI3K axis diverge from the canonical route and translocate to other cell organelles including the nucleus. The presence of phosphoinositides (PtdIns) inside the nucleus itself indicates the existence of a nuclear PI3K signalling. The nuclear localization of these signaling components is evident in regulating many nuclear processes like DNA replication, transcription, DNA repair, maintenance of genomic integrity, chromatin architecture, and cell cycle control. Here, our review intends to present a comprehensive overview of the nuclear functions of the PI3K-AKT-MTOR signaling biomolecules.
    Keywords:  MTORC2; PDK1; PTEN; RHEB; TSC1; inhibitors; nuclear entry; therapeutics
    DOI:  https://doi.org/10.1002/jcp.30782
  8. Biology (Basel). 2022 May 06. pii: 709. [Epub ahead of print]11(5):
    Single Gene Mutations in Pkd1 or Tsc2 Alter Extracellular Vesicle Production and Trafficking.
    Prashant Kumar, Fahad Zadjali, Ying Yao, Michael Köttgen, Alexis Hofherr, Kenneth W Gross, Darshan Mehta, John J Bissler.
      Patients with autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis complex (TSC) are born with normal or near-normal kidneys that later develop cysts and prematurely lose function. Both renal cystic diseases appear to be mediated, at least in part, by disease-promoting extracellular vesicles (EVs) that induce genetically intact cells to participate in the renal disease process. We used centrifugation and size exclusion chromatography to isolate the EVs for study. We characterized the EVs using tunable resistive pulse sensing, dynamic light scattering, transmission electron microscopy, and Western blot analysis. We performed EV trafficking studies using a dye approach in both tissue culture and in vivo studies. We have previously reported that loss of the Tsc2 gene significantly increased EV production and here demonstrate that the loss of the Pkd1 gene also significantly increases EV production. Using a cell culture system, we also show that loss of either the Tsc2 or Pkd1 gene results in EVs that exhibit an enhanced uptake by renal epithelial cells and a prolonged half-life. Loss of the primary cilia significantly reduces EV production in renal collecting duct cells. Cells that have a disrupted Pkd1 gene produce EVs that have altered kinetics and a prolonged half-life, possibly impacting the duration of the EV cargo effect on the recipient cell. These results demonstrate the interplay between primary cilia and EVs and support a role for EVs in polycystic kidney disease pathogenesis.
    Keywords:  autosomal dominant polycystic kidney disease (ADPKD); cystogenesis; extracellular vesicles (EVs); primary cilia; renal cyst; tuberous sclerosis complex (TSC)
    DOI:  https://doi.org/10.3390/biology11050709
  9. Pediatr Int. 2022 Jan;64(1): e15188
    Rapid regression everolimus therapy in a neonate with cardiac rhabdomyoma.
    Nilüfer Çetiner, Nazan Kavas, Osman Küçükosmanoğlu.
      
    Keywords:  cardiac rhabdomyoma; everolimus; neonate
    DOI:  https://doi.org/10.1111/ped.15188
  10. Eur J Cell Biol. 2022 May 19. pii: S0171-9335(22)00043-7. [Epub ahead of print]101(3): 151240
    Amino acids control blood glucose levels through mTOR signaling.
    Jialin Fan, Ziqiang Yuan, Stephen K Burley, Steven K Libutti, X F Steven Zheng.
      Amino Acids are not only major nutrient sources, but also serve as chemical signals to control cellular growth. Rab1A recently emerged as a key component in amino acid sensing and signaling to activate the mTOR complex1 (mTORC1). In a recently published study [1], we generated tamoxifen-inducible, conditional whole-body Rab1A knockout in adult mice. These mice are viable but develop hyperglycemia and glucose intolerance. Interestingly, Rab1A ablation selectively reduces insulin expression and pancreatic beta-cell population. Mechanistically, branched chain amino acids (BCAA), through the Rab1A-mTORC1 complex, promote the stability and nuclear localization of Pdx1, a master transcription factor that controls growth, function and identity of pancreatic beta-cells. These findings reveal a role and underlying mechanism by which amino acids control body's glucose level through a beta-cell specific function by the Rab1A-mTORC1-Pdx1 signaling axis, which has implications in both diabetes and cancer.
    Keywords:  Alpha cell; Amino acid; Beta cell; Cancer; Diabetes; Insulin; Islet; MTOR; Pancreas; Rab1A
    DOI:  https://doi.org/10.1016/j.ejcb.2022.151240
  11. Phys Biol. 2022 May 25.
    Spatiotemporal feedforward between PKM2 tetramers and mTORC1 prompts mTORC1 activation.
    Yu Xia, ShuMing Wang, Chunbo Song, Ruoyu Luo.
      Most mammalian cells couple glucose availability to anabolic processes via the mTORC1 pathway. However, the mechanism by which fluctuations in glucose availability are rapidly translated into mTORC1 signals remains elusive. Here, we show that cells rapidly respond to changes in glucose availability through the spatial coupling of mTORC1 and tetramers of the key glycolytic enzyme pyruvate kinase M2 (PKM2) on lysosomal surfaces in the late G1/S phases. The lysosomal localization of PKM2 tetramers enables rapid increases in local ATP concentrations around lysosomes to activate mTORC1, while bypassing the need to elevate global ATP levels in the entire cell. In essence, this spatial coupling establishes a feedforward loop to enable mTORC1 to rapidly sense and respond to changes in glucose availability. We further demonstrate that this mechanism ensures robust cell proliferation upon fluctuating glucose availability. Thus, we present mechanistic insights into the rapid response of the mTORC1 pathway to changes in glucose availability. The underlying mechanism may be applicable to the control of other cellular processes.
    Keywords:  Cancer metabolism; PKM2; Spatiotemporal Feedforward; mTORC1
    DOI:  https://doi.org/10.1088/1478-3975/ac7372
  12. iScience. 2022 May 20. 25(5): 104334
    Increased glycine contributes to synaptic dysfunction and early mortality in Nprl2 seizure model.
    Brianne Dentel, Lidiette Angeles-Perez, Chongyu Ren, Vikram Jakkamsetti, Andrew J Holley, Daniel Caballero, Emily Oh, Jay Gibson, Juan M Pascual, Kimberly M Huber, Benjamin P Tu, Peter T Tsai.
      Targeted therapies for epilepsies associated with the mTORC1 signaling negative regulator GATOR1 are lacking. NPRL2 is a subunit of the GATOR1 complex and mutations in GATOR1 subunits, including NPRL2, are associated with epilepsy. To delineate the mechanisms underlying NPRL2-related epilepsies, we created a mouse (Mus musculus) model with neocortical loss of Nprl2. Mutant mice have increased mTORC1 signaling and exhibit spontaneous seizures. They also display abnormal synaptic function characterized by increased evoked and spontaneous EPSC and decreased evoked and spontaneous IPSC frequencies, respectively. Proteomic and metabolomics studies of Nprl2 mutants revealed alterations in known epilepsy-implicated proteins and metabolic pathways, including increases in the neurotransmitter, glycine. Furthermore, glycine actions on the NMDA receptor contribute to the electrophysiological and survival phenotypes of these mice. Taken together, in this neuronal Nprl2 model, we delineate underlying molecular, metabolic, and electrophysiological mechanisms contributing to mTORC1-related epilepsy, providing potential therapeutic targets for epilepsy.
    Keywords:  metabolomics; molecular neuroscience; neuroscience; omics
    DOI:  https://doi.org/10.1016/j.isci.2022.104334
  13. J Mol Neurosci. 2022 May 27.
    Impact of Raptor and Rictor Deletion on Hippocampal Pathology Following Status Epilepticus.
    Christin M Godale, Emma V Parkins, Christina Gross, Steve C Danzer.
      Neuronal hyperactivation of the mTOR signaling pathway may play a role in driving the pathological sequelae that follow status epilepticus. Animal studies using pharmacological tools provide support for this hypothesis, however, systemic inhibition of mTOR-a growth pathway active in every mammalian cell-limits conclusions on cell type specificity. To circumvent the limitations of pharmacological approaches, we developed a viral/genetic strategy to delete Raptor or Rictor, inhibiting mTORC1 or mTORC2, respectively, from excitatory hippocampal neurons after status epilepticus in mice. Raptor or Rictor was deleted from roughly 25% of hippocampal granule cells, with variable involvement of other hippocampal neurons, after pilocarpine status epilepticus. Status epilepticus induced the expected loss of hilar neurons, sprouting of granule cell mossy fiber axons and reduced c-Fos activation. Gene deletion did not prevent these changes, although Raptor loss reduced the density of c-Fos-positive granule cells overall relative to Rictor groups. Findings demonstrate that mTOR signaling can be effectively modulated with this approach and further reveal that blocking mTOR signaling in a minority (25%) of granule cells is not sufficient to alter key measures of status epilepticus-induced pathology. The approach is suitable for producing higher deletion rates, and altering the timing of deletion, which may lead to different outcomes.
    Keywords:  Dentate granule cells; Temporal lobe epilepsy; c-Fos; mTOR; mTORC1; mTORC2
    DOI:  https://doi.org/10.1007/s12031-022-02030-w
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