bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2022–07–24
twelve papers selected by
  1. Confirmation of Decreased Rates of Cerebral Protein Synthesis In Vivo in a Mouse Model of Tuberous Sclerosis Complex.
  2. Giant cyst-like cortical tubers in an adult with tuberous sclerosis presenting as spastic tetraplegia.
  3. Monitoring and Managing Patients with Tuberous Sclerosis Complex: Current State of Knowledge.
  4. Synaptic hyperexcitability of cytomegalic pyramidal neurons contributes to epileptogenesis in tuberous sclerosis complex.
  5. A Multi-Centric Study Assessing Safety and Efficacy of Everolimus in Adult Chinese Patients With Tuberous Sclerosis Complex Associated Renal Angiomyolipomas.
  6. Case report: tuberous sclerosis and persistent hyperplastic primary vitreous.
  7. Development of an RHEB-Targeting Peptide To Inhibit mTORC1 Kinase Activity.
  8. Activating mTOR mutations are detrimental in nutrient-poor conditions.
  9. Brain Somatic Variant in Ras-Like Small GTPase RALA Causes Focal Cortical Dysplasia Type II.
  10. Use of Everolimus to treat cardiac rhabdomyomas and incessant arrhythmias in a newborn: Benefits and complications.
  11. mTORC1 activation induced proximal tubular damage via the pentose phosphate pathway in lupus nephritis.
  12. Glutamine Availability Regulates the Development of Aging Mediated by mTOR Signaling and Autophagy.
  1. eNeuro. 2022 Jul 18. pii: ENEURO.0480-21.2022. [Epub ahead of print]
    Confirmation of Decreased Rates of Cerebral Protein Synthesis In Vivo in a Mouse Model of Tuberous Sclerosis Complex.
    Rachel Michelle Saré, Anita Torossian, Inna Loutaev, Carolyn Beebe Smith.
      Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results in intellectual disability and, in ∼50% of patients, autism spectrum disorder. The protein products that are altered in TSC (TSC1 and TSC2) form a complex to inhibit the mammalian target of rapamycin [mTOR; mTOR complex 1 (mTORC1)] pathway. This pathway has been shown to affect the process of mRNA translation through its action on ribosomal protein S6 and 4-elongation binding protein 1. It is thought that mutations in the TSC proteins lead to upregulation of the mTORC1 pathway and consequently an increase in protein synthesis. Unexpectedly, our previous study of a mouse model of TSC (Tsc2Djk +/) demonstrated decreased in vivo rates of protein synthesis throughout the brain. In the present study, we confirm those results in another Tsc2+/- mouse model, one with a different mutation locus and on a mixed background (Tsc2Mjg +/-). We also examine mTORC1 signaling and possible effects of prior isoflurane anesthesia. Because measurements of protein synthesis rates in vivo require surgical preparation of the animal and anesthesia, we examine mTORC1 signaling pathways both under baseline conditions and following recovery from anesthesia. Our results demonstrate regionally selective effects of prior anesthesia. Overall, our results in both in vivo models suggest differences to the central hypothesis regarding TSC and show the importance of studying protein synthesis in vivo Significance StatementProtein synthesis is an important process for brain function. In the disorder, tuberous sclerosis complex (TSC), the inhibition of the mammalian target of rapamycin (mTOR) pathway is reduced and this is thought to lead to excessive protein synthesis. Most studies of protein synthesis in models of TSC have been conducted in vitro We report here confirmation of our previous in vivo study showing decreased brain protein synthesis rates in a second mouse model of TSC, results counter to the central hypothesis regarding TSC. We also explore the possible influence of prior isoflurane exposure on signaling pathways involved in regulation of protein synthesis. This study highlights a novel aspect of TSC and the importance of studying cellular processes in vivo.
    Keywords:  mTOR; protein synthesis; tuberous sclerosis
    DOI:  https://doi.org/10.1523/ENEURO.0480-21.2022
  2. Ann Med Surg (Lond). 2022 Jul;79 104024
    Giant cyst-like cortical tubers in an adult with tuberous sclerosis presenting as spastic tetraplegia.
    Habib Ahmad Esmat.
       Introduction and importance: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations in TSC1 or TSC2 genes, resulting in benign lesions that involve multiple organs including the central nerves system.
    Case presentation: A 39-year-old male of known TSC presented with inability to walk for two months. On physical examination, he was consciously oriented and cooperative, but he had spastic tetraparesis in the muscle-motor examination. On brain imaging, cystic lesions of various sizes in the supra and infratentorial regions were observed, consistent with giant cyst-like tubers. However, they could not differentiate from TSC related brain tumors based on the imaging findings. He underwent surgical intervention to resect/evacuate the large cystic lesion, which had the mass effects on the brain stem. The pathologic examinations revealed no malignant changes.
    Clinical discussion: Although the cyst-like lesions in the cortex and white matter have been reported in several previous studies of TSC, they usually had a small size and similar intensity to CSF on T2- weighted MRI and low intensity on FLAIR images.
    Conclusion: Giant cyst-like cortical tubers are exceedingly rare and atypical findings of tuberous sclerosis complex, which are usually associated with epilepsy and neurological deficits. Though many authors recommend the brain MRI as a screening tool for patients with TSC once every 1-3 years until the age of 25, our report showed that the brain lesions may develop in patients with TSC even after the age of 25. Thus, the MRI should be used periodically in all patients with TSC to timely detect the brain lesions and prevent the patient's disability. Surgical resection is the mainstay of treatment for the symptomatic cystic-like cortical tuber; however, it may recur after resection.
    Keywords:  Giant cyst-like tubers; Spastic tetraplegia; Tuberous sclerosis complex
    DOI:  https://doi.org/10.1016/j.amsu.2022.104024
  3. J Multidiscip Healthc. 2022 ;15 1469-1480
    Monitoring and Managing Patients with Tuberous Sclerosis Complex: Current State of Knowledge.
    Inês Gomes, Joana Jesus Ribeiro, Filipe Palavra.
      Tuberous sclerosis complex (TSC) is a rare genetic disease of autosomal dominant transmission that, in most cases, results from the presence of pathogenic variants of the TSC1 or TSC2 genes, encoding hamartin and tuberin, respectively. It is a multisystemic disease, affecting most frequently the brain, skin, kidney, and heart. The wide variety of possible clinical manifestations, given this multisystem dimension, makes the follow-up of patients with TSC an exercise of multidisciplinarity. In fact, these patients may require the intervention of various medical specialties, which thus have to combine their efforts to practice a medicine that is truly holistic. The past few years have witnessed a dramatic leap not only in the diagnosis and management of TSC patients, with standard monitoring recommendations, but also in the therapeutic field, with the use of mTORC1 inhibitors. In this article, we review the clinical manifestations associated with TSC, as well as the treatment and follow-up strategies that should be implemented, from a multidisciplinary perspective.
    Keywords:  care management; multidisciplinary communications; patient; tuberous sclerosis complex
    DOI:  https://doi.org/10.2147/JMDH.S266990
  4. Cell Rep. 2022 Jul 19. pii: S2211-1247(22)00887-7. [Epub ahead of print]40(3): 111085
    Synaptic hyperexcitability of cytomegalic pyramidal neurons contributes to epileptogenesis in tuberous sclerosis complex.
    Xiaoping Wu, Alexander A Sosunov, Wudu Lado, Jia Jie Teoh, Ahrom Ham, Hongyu Li, Osama Al-Dalahmah, Brian J A Gill, Ottavio Arancio, Catherine A Schevon, Wayne N Frankel, Guy M McKhann, David Sulzer, James E Goldman, Guomei Tang.
      Tuberous sclerosis complex (TSC) is a developmental disorder associated with epilepsy, autism, and cognitive impairment. Despite inactivating mutations in the TSC1 or TSC2 genes and hyperactive mechanistic target of rapamycin (mTOR) signaling, the mechanisms underlying TSC-associated neurological symptoms remain incompletely understood. Here we generate a Tsc1 conditional knockout (CKO) mouse model in which Tsc1 inactivation in late embryonic radial glia causes social and cognitive impairment and spontaneous seizures. Tsc1 depletion occurs in a subset of layer 2/3 cortical pyramidal neurons, leading to development of cytomegalic pyramidal neurons (CPNs) that mimic dysplastic neurons in human TSC, featuring abnormal dendritic and axonal overgrowth, enhanced glutamatergic synaptic transmission, and increased susceptibility to seizure-like activities. We provide evidence that enhanced synaptic excitation in CPNs contributes to cortical hyperexcitability and epileptogenesis. In contrast, astrocytic regulation of synapse formation and synaptic transmission remains unchanged after late embryonic radial glial Tsc1 inactivation, and astrogliosis evolves secondary to seizures.
    Keywords:  CP: Neuroscience; astrogliosis; cortical hyperexcitability; cytomegalic dysplastic neurons; epileptogenesis; tuberous sclerosis complex
    DOI:  https://doi.org/10.1016/j.celrep.2022.111085
  5. Front Oncol. 2022 ;12 871723
    A Multi-Centric Study Assessing Safety and Efficacy of Everolimus in Adult Chinese Patients With Tuberous Sclerosis Complex Associated Renal Angiomyolipomas.
    Wenda Wang, Gang Guo, Guohai Shi, Xin Wei, Zhiquan Hu, Hanzhong Li, Xu Zhang, Dingwei Ye, Yushi Zhang.
       Background: Everolimus has been approved in China for adult patients with TSC-AML (tuberous sclerosis associated renal angiomyolipomas) not requiring immediate surgery and has been previously shown to be an effective treatment option for TSC-AML in the Chinese population.
    Methods: This is an open label, single arm, multi-center Phase IV post-approval commitment study to further assess the safety and efficacy of everolimus in patients with TSC-AML who do not require immediate surgical intervention. The primary outcome was to evaluate the safety of everolimus while the secondary outcome was to evaluate AML response.
    Results: Treatment with everolimus was associated with a clinically meaningful best overall AML response rate of 70% (95% CI: 53.5, 83.4). Of the 38 evaluable patients, 37 (97%) patients experienced a reduction in the sum of volumes of target angiomyolipoma lesions relative to baseline. At Week 12 (n=38), the median percentage change in sum of target AML volume was -56.60%, which further changed by -59.96% at Week 24 (n=38), and by -64.41% at Week 48 (n=22). Throughout the study, renal function remained relatively stable. Patients with TSC associated lymphangiomyomatosis (LAM) (N=13) demonstrated a lower than expected rate of decline in pulmonary function tests (PFTs). Everolimus was generally well tolerated with no significant safety findings in Chinese patients. Most of the adverse events were of grade 1-2, and manageable with appropriate dose adjustments and supportive therapies. There were no treatment discontinuation due to AE and no treatment death was reported.
    Conclusions: Based on the efficacy and safety data presented in this study, the overall clinical benefit/risk assessment further supports the use of everolimus as a viable treatment option for Chinese patients with TSC-AML.
    Keywords:  angiomyolipoma; efficacy and safety; everolimus; gender; tuberous sclerosis complex
    DOI:  https://doi.org/10.3389/fonc.2022.871723
  6. BMC Ophthalmol. 2022 Jul 16. 22(1): 308
    Case report: tuberous sclerosis and persistent hyperplastic primary vitreous.
    Hayley Wong, Sarah Bowie, Shona Handisides, Julia Escardó-Paton.
       BACKGROUND: Persistent hyperplastic primary vitreous (PHPV) in a patient with tuberous sclerosis (TS) has been described in one previous case report in 1999. Otherwise, there is no literature around this potential association. We describe a case of an infant with TS and PHPV.
    CASE PRESENTATION: An 11-month old male was under investigation for leukocoria, microphthalmia and suspected PHPV after being seen in ophthalmology clinic. He presented to hospital with seizures and was diagnosed with TS on imaging. Imaging also showed the known microphthalmia and a mass associated with the lens. Subsequent paediatric ophthalmology review and examination under anaesthesia confirmed microphthalmia, PHPV and a retrolental mass which was thought to represent total retinal detachment or a retinal hamartoma within a retinal detachment.
    CONCLUSIONS: This is the second case report of PHPV in a patient with TS. The previous case report postulated that the atypical location of the retinal hamartoma was secondary to the abnormal globe development in PHPV.
    Keywords:  Case report; Persistent hyperplastic primary vitreous; Retinal hamartoma; Tuberous sclerosis
    DOI:  https://doi.org/10.1186/s12886-022-02526-4
  7. ACS Omega. 2022 Jul 12. 7(27): 23479-23486
    Development of an RHEB-Targeting Peptide To Inhibit mTORC1 Kinase Activity.
    Raef Shams, Yoshihiro Ito, Hideyuki Miyatake.
      In cancer, the mechanistic/mammalian target of rapamycin complex-1 (mTORC1) is hyperactivated to promote survival under adverse conditions. The kinase activity of mTORC1 is activated by small-GTPase RHEB-GTP. Therefore, a new modality to inhibit mTORC1 activity has emerged, through intercepting RHEB. However, due to the relatively large contact area involved in the interaction between RHEB and mTORC1, facilitating this inhibition through small molecules has been challenging. Here, we report the development of a peptide that can inhibit the RHEB-mTORC1 interaction. The peptide, P1_WT, was designed based on the α-helix (aa 101-115) of the N-heat domain of mTOR to interact with switch II of RHEB. P1_WT bound to RHEB (K D = 0.14 μM) and inhibited RHEB-mTORN-heat interaction (IC50 = 0.33 μM) in vitro. Consequently, P1_WT inhibited mTORC1 activity at a sub-micromolar level (IC50 ∼ 0.3 μM). P1_WT was predicted to be cell-permeable due to the rich content of arginine (23%), enhancing the intracellular translocation. These results show that P1_WT is a potential compound to further develop inhibitors for mTORC1 by intercepting RHEB from mTORC1.
    DOI:  https://doi.org/10.1021/acsomega.2c01865
  8. Cancer Res. 2022 Jul 22. pii: CAN-22-0121. [Epub ahead of print]
    Activating mTOR mutations are detrimental in nutrient-poor conditions.
    Agata A Bielska, Caitlin F Harrigan, Yeon Ju Kyung, Quaid Morris, Wilhelm Palm, Craig B Thompson.
      The mechanistic target of rapamycin (mTOR) is a key regulator of cell growth that integrates growth factor signaling and nutrient availability and is a downstream effector of oncogenic receptor tyrosine kinases (RTKs) and PI3K/Akt signaling. Thus, activating mTOR mutations would be expected to enhance growth in many tumor types. However, tumor sequencing data has shown that mTOR mutations are enriched only in renal clear cell carcinoma, a clinically hypervascular tumor unlikely to be constrained by nutrient availability. To further define this cancer type-specific restriction, we studied activating mutations in mTOR. All mTOR mutants tested enhanced growth in a cell type agnostic manner under nutrient-replete conditions but were detrimental to cell survival in nutrient-poor conditions. Consistently, analysis of tumor data demonstrated that oncogenic mutations in the nutrient-sensing arm of the mTOR pathway display a similar phenotype and were exceedingly rare in human cancers of all types. Together, these data suggest that maintaining the ability to turn off mTOR signaling in response to changing nutrient availability is retained in most naturally occurring tumors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0121
  9. Front Behav Neurosci. 2022 ;16 919485
    Brain Somatic Variant in Ras-Like Small GTPase RALA Causes Focal Cortical Dysplasia Type II.
    Han Xu, Kai Gao, Qingzhu Liu, Tianshuang Wang, Zhongbin Zhang, Lixin Cai, Ye Wu, Yuwu Jiang.
       Purpose: In our group's previous study, we performed deep whole-exome sequencing and targeted amplicon sequencing in the postoperative brain tissue of epilepsy patients with focal cortical dysplasia type II (FCD II). We identified the first somatic variant of RALA in the brain tissue of a child with FCD type IIb. RALA encodes a small GTPase of the Ras superfamily. To date, the role of RALA in brain development is not yet known. In this study, we reported that the RALA somatic variant led to FCD type II through activation of the mammalian target of rapamycin (mTOR) pathways.
    Materials and Methods: HEK293T cells were transfected in vitro to analyze the expression of the RalA protein, as well as phosphorylated S6 (P-S6), one of the major markers of mTOR pathway activation, RalA GTPase activity, and the interaction between RalA and its downstream binding effectors. In vivo, wild-type, and mutant RALA plasmids were transfected into the local cortex of mice using in utero electroporation to evaluate the effect of RALA c.G482A on neuronal migration.
    Results: The RALA c.G482A mutation increased RalA protein expression, the abnormal activation of the mTOR pathways, RalA GTPase activity, and binding to downstream effectors. RALA c.G482A local transfection in the embryonic brain in utero induced abnormal cortical neuron migration in mice.
    Conclusion: This study demonstrated for the first time that the somatic gain-of-function variant of RALA activates the mTOR pathway and leads to neuronal migration disorders in the brain, facilitating the development of FCD II. Therefore, RALA brain somatic mutation may be one of the pathogenic mechanisms leading to FCD II, which is always related to drug-resistant epilepsy in children. However, more somatic variations of this gene are required to be confirmed in more FCD II patient brain samples.
    Keywords:  FCD II; RalA; mTOR pathway; pediatric drug-resistant epilepsy; somatic mutation
    DOI:  https://doi.org/10.3389/fnbeh.2022.919485
  10. Ann Pediatr Cardiol. 2022 Jan-Feb;15(1):15(1): 58-60
    Use of Everolimus to treat cardiac rhabdomyomas and incessant arrhythmias in a newborn: Benefits and complications.
    Eyal Sagiv, Sathish Mallenahalli Chikkabyrappa, Jeffrey Conwell, Mark Lewin, Terrence Un Hoong Chun.
      We report treating a term neonate with tuberous sclerosis and giant rhabdomyomas who presented with incessant supraventricular tachycardia with Everolimus. The treatment was efficient in reducing tumor size and assisted as an adjunct therapy in controlling arrhythmia and limiting preexcitation. Treatment was challenged by difficulty to achieve stable drug level and limited by neutropenia as a serious side effect.
    Keywords:  Everolimus; Wolff-Parkinson-White; rhabdomyomas
    DOI:  https://doi.org/10.4103/apc.apc_11_21
  11. Free Radic Biol Med. 2022 Jul 18. pii: S0891-5849(22)00492-0. [Epub ahead of print]
    mTORC1 activation induced proximal tubular damage via the pentose phosphate pathway in lupus nephritis.
    Zhaomin Mao, Ying Tan, Juan Tao, Linlin Li, Feng Yu, Minghui Zhao.
      More recent studies suggested that metabolic disorders could contribute to the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). The present work aimed at identifying metabolic reprogramming in the kidney of lupus nephritis via proteomics and investigating the potential regulatory mechanism. The proteomic studies on the renal biopsies revealed that the pentose phosphate pathway (PPP) was significantly enriched in the kidneys of LN patients compared with normal controls (NCs). Immunohistochemical stanning of glucose-6-phosphate dehydrogenase (G6PD), the key rate-limiting enzyme of PPP, verify the results of proteomics. We found that G6PD was highly expressed in the kidneys of LN patients and correlated with several clinicopathological indices. The univariate Cox regression analysis (HR, 95%CI, 1.877 (1.059-3.328), P = 0.031) and Kaplan-Meier (KM) analysis (P = 0.028) suggested that high G6PD expression in the tubulointerstitial area was a risk factor for worse prognosis. Moreover, the Gene set enrichment analysis (GSEA) demonstrated that the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway ranked first in the kidneys of LN patients with high G6PD expression and G6PD was co-localized with mTORC1 activation in the tubule. Immunoglobulin G (IgG) isolated from LN patients significantly activated the mTORC1 pathway and increased G6PD expression, G6PD activity, NADPH production, NADPH oxidase 2 (NOX2) expression, reactive oxygen species (ROS) production, and cell apoptosis in tubule cells in vitro. The above phenotypes were partially rescued after the addition of rapamycin or knock-down of G6PD. Overall, our study suggested that renal G6PD expression was associated with the overall enhanced disease activity and worse renal prognosis. mTORC1 activation might be involved in IgG-LN-induced tubular damage via PPP.
    Keywords:  G6PD; Lupus nephritis; Pentose phosphate pathway; mTORC1
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.07.010
  12. Front Pharmacol. 2022 ;13 924081
    Glutamine Availability Regulates the Development of Aging Mediated by mTOR Signaling and Autophagy.
    Jiao Zhou, Honghan Chen, Jintao Du, Haoran Tai, Xiaojuan Han, Ning Huang, Xiaobo Wang, Hui Gong, Mingyao Yang, Hengyi Xiao.
      Glutamine is a conditionally essential amino acid involved in energy production and redox homeostasis. Aging is commonly characterized by energy generation reduction and redox homeostasis dysfunction. Various aging-related diseases have been reported to be accompanied by glutamine exhaustion. Glutamine supplementation has been used as a nutritional therapy for patients and the elderly, although the mechanism by which glutamine availability affects aging remains elusive. Here, we show that chronic glutamine deprivation induces senescence in fibroblasts and aging in Drosophila melanogaster, while glutamine supplementation protects against oxidative stress-induced cellular senescence and rescues the D-galactose-prompted progeria phenotype in mice. Intriguingly, we found that long-term glutamine deprivation activates the Akt-mTOR pathway, together with the suppression of autolysosome function. However, the inhibition of the Akt-mTOR pathway effectively rescued the autophagy impairment and cellular senescence caused by glutamine deprivation. Collectively, our study demonstrates a novel interplay between glutamine availability and the aging process. Mechanistically, long-term glutamine deprivation could evoke mammalian target of rapamycin (mTOR) pathway activation and autophagy impairment. These findings provide new insights into the connection between glutamine availability and the aging process.
    Keywords:  aging; autophagy; cellular senescence; glutamine; mTOR
    DOI:  https://doi.org/10.3389/fphar.2022.924081
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