bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2022‒06‒12
nine papers selected by
Marti Cadena Sandoval
metabolic-signalling.eu
  1. New scalp swelling in a child with tuberous sclerosis complex.
  2. Stereoelectroencephalography in the very young: Case report.
  3. Ketogenic Diet Therapy for Drug-Resistant Epilepsy and Cognitive Impairment in Children With Tuberous Sclerosis Complex.
  4. Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the 5XFAD Alzheimer's Disease Model.
  5. Contemporary mTOR inhibitor scaffolds to diseases breakdown: A patent review (2015-2021).
  6. Deletion of Rheb1 in Osteocytes Leads to Osteopenia Characterized by Reduced Bone Formation and Enhanced Bone Resorption.
  7. High glutamine suppresses osteogenesis through mTORC1-mediated inhibition of the mTORC2/AKT-473/RUNX2 axis.
  8. Loss of 4E-BP converts cerebellar long-term depression to long-term potentiation.
  9. Detection of brain somatic variation in epilepsy-associated developmental lesions.
  1. Arch Dis Child. 2022 Jun 09. pii: archdischild-2022-324105. [Epub ahead of print]
    New scalp swelling in a child with tuberous sclerosis complex.
    Vivek Mundada, Pawankumar Maniyar.
      
    Keywords:  Dermatology; Neurology
    DOI:  https://doi.org/10.1136/archdischild-2022-324105
  2. Epilepsy Behav Rep. 2022 ;19 100552
    Stereoelectroencephalography in the very young: Case report.
    Joshua Katz, Caren Armstrong, Svetlana Kvint, Benjamin C Kennedy.
      Stereoelectroencephalography (SEEG) is an increasingly popular invasive monitoring approach to epilepsy surgery in patients with drug-resistant epilepsies. The technique allows a three-dimensional definition of the epileptogenic zones (EZ) in the brain. It has been shown to be safe and effective in adults and older children but has been used sparingly in children less than two years old due to concerns about pin fixation in thin bone, registration accuracy, and bolt security. As such, most current series of pediatric invasive EEG explorations do not include young participants, and, when they do, SEEG is often not utilized for these patients. Recent national survey data further suggests SEEG is infrequently utilized in very young patients. We present a novel case of SEEG used to localize the EZ in a 17-month-old patient with thin cranial bone, an open fontanelle, and severe drug-resistant epilepsy due to tuberous sclerosis complex (TSC), with excellent accuracy, surgical results, and seizure remission.
    Keywords:  Neurosurgery; Pediatric; Robotic; Stereoelectroencephalography; Tuberous sclerosis
    DOI:  https://doi.org/10.1016/j.ebr.2022.100552
  3. Front Neurol. 2022 ;13 863826
    Ketogenic Diet Therapy for Drug-Resistant Epilepsy and Cognitive Impairment in Children With Tuberous Sclerosis Complex.
    Yu Fang, Dan Li, Man Wang, Xia Zhao, Jing Duan, Qiang Gu, Baomin Li, Jian Zha, Daoqi Mei, Guangbo Bian, Man Zhang, Huiting Zhang, Junjie Hu, Liu Yang, Lifei Yu, Hua Li, Jianxiang Liao.
      Objective: Tuberous sclerosis complex (TSC) is a rare disease with a high risk of epilepsy and cognitive impairment in children. Ketogenic diet (KD) therapy has been consistently reported to be beneficial to TSC patients. In this study, we aimed to investigate the efficacy and safety of KD in the treatment of drug-resistant epilepsy and cognitive impairment in children with TSC.Methods: In this multicenter study, 53 children (33 males and 20 females) with drug-resistant epilepsy or cognitive impairment caused by TSC were retrospectively recruited from 10 hospitals from January 1, 2010, to December 31, 2020. Intention-to-treat analysis was used to evaluate seizure reduction and cognition improvement as outcomes after KD therapy.
    Results: Of the 53 TSC patients included, 51 failed to be seizure-free with an average of 5.0 (range, 4-6) different anti-seizure medications (ASMs), before KD therapy. Although the other two patients achieved seizure freedom before KD, they still showed psychomotor development delay and electroencephalogram (EEG) abnormalities. At 1, 3, 6, and 12 months after the KD therapy, 51 (100%), 46 (90.2%), 35 (68.6%), and 16 patients (31.4%) remained on the diet therapy, respectively. At these time points, there were 26 (51.0%), 24 (47.1%), 22 (43.1%) and 13 patients (25.5%) having ≥50% reductions in seizure, including 11 (21.6%), 12 (23.5%), 9 (17.6%) and 3 patients (5.9%) achieving seizure freedom. In addition, of 51 patients with psychomotor retardation, 36 (36 of 51, 70.6%) showed cognitive and behavioral improvements. During the KD therapy, no serious side effects occurred in any patient. The most common side effects were gastrointestinal disturbance (20 of 53, 37.7%) and hyperlipidemia (6 of 53, 11.3%). The side effects were gradually relieved after adjustment of the ketogenic ratio and symptomatic treatment.
    Conclusion: KD is an effective and safe treatment for TSC-related drug-resistant epilepsy and cognitive impairment in children. KD can reduce seizure frequency and may potentially improve cognition and behavior.
    Keywords:  children; cognitive impairment; comorbidity; drug-resistant epilepsy; ketogenic diet; multi-center clinical trial; tuberous sclerosis complex
    DOI:  https://doi.org/10.3389/fneur.2022.863826
  4. J Neurosci. 2022 Jun 02. pii: JN-RM-2427-21. [Epub ahead of print]
    Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the 5XFAD Alzheimer's Disease Model.
    Qian Shi, Cheng Chang, Afaf Saliba, Manzoor A Bhat.
      The mechanistic Target of Rapamycin (mTOR) signaling pathway plays a major role in key cellular processes including metabolism and differentiation; however, the role of mTOR in microglia and its importance in Alzheimer's disease (AD) has remained largely uncharacterized. We report that selective loss of Tsc1, a negative regulator of mTOR, in microglia in mice of both sexes, caused mTOR activation and upregulation of Trem2 with enhanced β-Amyloid clearance, reduced spine loss, and improved cognitive function in the 5XFAD AD mouse model. Combined loss of Tsc1 and Trem2 in microglia led to reduced β-Amyloid clearance and increased Aβ plaque burden revealing that Trem2 functions downstream of mTOR. Tsc1 mutant microglia showed increased phagocytosis with upregulation of CD68 and Lamp1 lysosomal proteins. In vitro studies using Tsc1-deficient microglia revealed enhanced endocytosis of the lysosomal tracker indicator Green DND-26 suggesting increased lysosomal activity. Incubation of Tsc1-deficient microglia with fluorescent-labeled Aβ revealed enhanced Aβ uptake and clearance, which was blunted by rapamycin, an mTOR inhibitor. In vivo treatment of mice of relevant genotypes in the 5XFAD background with rapamycin, affected microglial activity, decreased Trem2 expression and reduced Aβ clearance causing an increase in Aβ plaque burden. Prolonged treatment with rapamycin caused even further reduction of mTOR activity, reduction in Trem2 expression, and increase in Aβ levels. Together, our findings reveal that mTOR signaling in microglia is critically linked to Trem2 regulation and lysosomal biogenesis, and that the up-regulation of Trem2 in microglia through mTOR activation could be exploited towards better therapeutic avenues to β-Amyloid-related AD pathologies.Significance statement:mTOR signaling pathway is a key regulator for major cellular metabolic processes. However, the link between mTOR signaling and AD is not well understood. In this study, we provide compelling in vivo evidence that mTOR activation in microglia would benefit β-Amyloid related AD pathologies, as it upregulates Trem2, a key receptor for β-Amyloid plaque uptake. Inhibition of mTOR pathway with rapamycin, a well-established immunosuppressant, downregulated Trem2 in microglia and reduced β-Amyloid plaque clearance indicating that mTOR inactivation may be detrimental in β-Amyloid-associated AD patients. This finding will have a significant public health impact and benefit, regarding the usage of rapamycin in AD patients, which we believe will aggravate the β-Amyloid-related AD pathologies.
    DOI:  https://doi.org/10.1523/JNEUROSCI.2427-21.2022
  5. Eur J Med Chem. 2022 May 28. pii: S0223-5234(22)00400-7. [Epub ahead of print]238 114498
    Contemporary mTOR inhibitor scaffolds to diseases breakdown: A patent review (2015-2021).
    Patrik Oleksak, Eugenie Nepovimova, Zofia Chrienova, Kamil Musilek, Jiri Patocka, Kamil Kuca.
      Mechanistic target of rapamycin (mTOR) is a highly conserved protein kinase acting as a central regulator of cell functions. The kinase forms two distinct mTOR complexes termed as mTORC1 and mTORC2. Dysregulation of mTOR activity is associated with various pathological conditions. Inhibition of overactivated mTOR represent a rational approach in the treatment of numerous human diseases. Rapamycin is a potent natural inhibitor of mTOR exhibiting significant antitumor and immunosuppressive activity. Derivatization of rapamycin provided rapalogs, the first generation of mTOR inhibitors that selectively inhibit mTORC1 activity. Further interest of research community resulted in creation of the second generation of mTOR inhibitors involving both, mTOR kinase inhibitors and dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitors. Recently, combining advances of first and second generation of mTOR inhibitors yielded in the third generation of inhibitors termed as rapalinks. Nowadays, novel inhibitors belonging to all of the three generations are still under development. These inhibitors help us better to understand role of mTOR in mTOR signaling pathway as well as in diverse human diseases. In this review, we summarize recent reported mTOR inhibitors or methods of use thereof in the treatment of various diseases.
    Keywords:  Dual PI3K/mTOR inhibitors; PI3K/AKT/mTOR signaling pathway; Rapalinks; Rapalogs; Rapamycin; mTOR inhibitor; mTOR kinase inhibitors
    DOI:  https://doi.org/10.1016/j.ejmech.2022.114498
  6. DNA Cell Biol. 2022 Jun 10.
    Deletion of Rheb1 in Osteocytes Leads to Osteopenia Characterized by Reduced Bone Formation and Enhanced Bone Resorption.
    Jun Yang, Wuju Zhang, Eryong Lai, Wen Liu, Pinglin Lai, Zhipeng Zou, Weidong Wang, Xiaochun Bai.
      Ras homologue enriched in brain 1 (Rheb1), an upstream activator of the mechanistic target of rapamycin complex 1 (mTORC1), is known to modulate various cellular processes. However, its impact on bone metabolism in vivo remains unknown. The study aimed at understanding the role of Rheb1 on bone homeostasis. We measured the serum parameters and performed histomorphometry, quantitative real-time polymerase chain reaction, and Western blotting, along with the generation of mouse gene knockout (KO) model, and conducted a microcomputed tomography analysis and tartrate-resistant acid phosphatase staining, to delineate the impacts of Rheb1 on bone homeostasis. In the Rheb1 KO mice, the results showed that Rheb1 KO caused significant damage to the bone microarchitecture, indicating that mTORC1 activity was essential for the regulation of bone homeostasis. Specifically, suppressed mineralization activity in primary osteoblasts and a decreased osteoblast number were observed in the Rheb1 KO mice, demonstrating that loss of Rheb1 led to impaired osteoblastic differentiation. Furthermore, the higher apoptotic ratio in Rheb1-null osteocytes could promote Tnfsf11 expression and lead to an increase in osteoclasts, indicating increased bone resorption activity in the KO mice. The findings confirmed that Rheb1 deletion in osteoblasts/osteocytes led to osteopenia due to impaired bone formation and enhanced bone resorption.
    Keywords:  Rheb1; mature osteoblast; osteocyte; osteopenia
    DOI:  https://doi.org/10.1089/dna.2021.0874
  7. Cell Death Discov. 2022 Jun 07. 8(1): 277
    High glutamine suppresses osteogenesis through mTORC1-mediated inhibition of the mTORC2/AKT-473/RUNX2 axis.
    Meher Bolisetti Gayatri, Navya Naidu Gajula, Suresh Chava, Aramati B M Reddy.
      Activation of the key nutrient cellular sensors mTORC1 and mTORC2 directs the fate of mesenchymal stromal cells (MSCs). Here, we report that glutamine regulates crosstalk between mTOR complexes and lineage commitment of MSCs independent of glucose concentration. High glutamine-induced mTORC1 hyperactivation resulted in the suppression of mTORC2, which otherwise stabilizes RUNX2 via GSK3β inhibition through pAKT-473. Activation of GSK3β resulted in the ubiquitination of RUNX2, a key transcription factor for the osteogenic commitment of MSCs. However, low glutamine conditions inhibit mTORC1 hyperactivation followed by increased mTORC2 activation and RUNX2 stabilization. Under diabetic/high-glucose conditions, glutamine-triggered hyperactivation of mTORC1 resulted in mTORC2 suppression, and active GSK3β led to suppression of RUNX2. Activation of p-AMPK by metformin inhibits high glutamine-induced mTORC1 hyperactivation and rescues RUNX2 through the mTORC2/AKT-473 axis. Collectively, our study indicates the role of glutamine in modulating MSC fate through cross-talk between mTOR complexes by identifying a critical switch in signaling. It also shows the importance of glutamine in modulating molecular cues (mTORC1/p-70S6K/mTORC2/RUNX2) that are involved in driving diabetes-induced bone adipogenesis and other secondary complications.
    DOI:  https://doi.org/10.1038/s41420-022-01077-3
  8. Cell Rep. 2022 Jun 07. pii: S2211-1247(22)00688-X. [Epub ahead of print]39(10): 110911
    Loss of 4E-BP converts cerebellar long-term depression to long-term potentiation.
    Natasha Saviuk, Yumaine Chong, Peng Wang, Sara Bermudez, Zhe Zhao, Arjun A Bhaskaran, Derek Bowie, Nahum Sonenberg, Ellis Cooper, A Pejmun Haghighi.
      Genetic perturbances in translational regulation result in defects in cerebellar motor learning; however, little is known about the role of translational mechanisms in the regulation of cerebellar plasticity. We show that genetic removal of 4E-BP, a translational suppressor and target of mammalian target of rapamycin complex 1, results in a striking change in cerebellar synaptic plasticity. We find that cerebellar long-term depression (LTD) at parallel fiber-Purkinje cell synapses is converted to long-term potentiation in 4E-BP knockout mice. Biochemical and pharmacological experiments suggest that increased phosphatase activity largely accounts for the defects in LTD. Our results point to a model in which translational regulation through the action of 4E-BP plays a critical role in establishing the appropriate kinase/phosphatase balance required for normal synaptic plasticity in the cerebellum.
    Keywords:  4E-BP; CP: Neuroscience; LTD; PP2A; Purkinje cells; autism; cerebellum; mTOR; phosphatase kinase balance; synaptic plasticity; translation
    DOI:  https://doi.org/10.1016/j.celrep.2022.110911
  9. Epilepsia. 2022 Jun 10.
    Detection of brain somatic variation in epilepsy-associated developmental lesions.
    Tracy A Bedrosian, Katherine E Miller, Olivia E Grischow, Kathleen M Schieffer, Stephanie LaHaye, Hyojung Yoon, Anthony R Miller, Jason Navarro, Jesse Westfall, Kristen Leraas, Samantha Choi, Rachel Williamson, James Fitch, Benjamin J Kelly, Peter White, Kristy Lee, Sean McGrath, Catherine E Cottrell, Vincent Magrini, Jeffrey Leonard, Jonathan Pindrik, Ammar Shaikhouni, Daniel R Boué, Diana L Thomas, Christopher R Pierson, Richard K Wilson, Adam P Ostendorf, Elaine R Mardis, Daniel C Koboldt.
      OBJECTIVE: Epilepsy-associated developmental lesions, including malformations of cortical development and low-grade developmental tumors, represent a major cause of drug-resistant seizures requiring surgical intervention in children. Brain-restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified.METHODS: We enrolled 50 children undergoing epilepsy surgery into a translational research study. Resected tissue was divided for clinical neuropathologic evaluation and genomic analysis. We performed exome and RNA-sequencing to identify somatic variation and confirmed our findings using high-depth targeted DNA sequencing.
    RESULTS: We uncovered candidate disease-causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). In agreement with previous studies, we identified somatic variation affecting SLC35A2 and MTOR pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) Type I FCD patients. Somatic variation of MAPK pathway genes (i.e., FGFR1, FGFR2, BRAF, KRAS) was associated with low-grade epilepsy-associated developmental tumors. RNA-sequencing enabled the detection of somatic structural variation that would have otherwise been missed, and which accounted for over one-half of epilepsy-associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease-causing variants in genes not yet associated with focal cortical dysplasia.
    SIGNIFICANCE: These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes.
    Keywords:  LEAT; brain development; epilepsy; focal cortical dysplasia; somatic mosaicism
    DOI:  https://doi.org/10.1111/epi.17323
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