bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2022–03–27
twelve papers selected by
  1. Focal Epilepsy in Children With Tuberous Sclerosis Complex: Does Vigabatrin Control Focal Seizures?
  2. Prenatal MR Imaging Phenotype of Fetuses with Tuberous Sclerosis: An Institutional Case Series and Literature Review.
  3. Neonatal rhabdomyoma with cardiac dysfunction: favourable response to sirolimus.
  4. Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice.
  5. Multiple Interventions to Thoracoabdominal Aortic Aneurysm in a Child with Tuberous Sclerosis.
  6. Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning.
  7. Effects of mTORC1 inhibition on proteasome activity and levels.
  8. Emerging Roles for Mammalian Target of Rapamycin (mTOR) Complexes in Bladder Cancer Progression and Therapy.
  9. S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions.
  10. The central moTOR of metabolism.
  11. Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy.
  12. Rapamycin Pretreatment Attenuates High Glucose-induced Alteration of Synaptic Transmission in Hippocampal Dentate Gyrus Neurons.
  1. J Child Neurol. 2022 Mar 23. 8830738211048326
    Focal Epilepsy in Children With Tuberous Sclerosis Complex: Does Vigabatrin Control Focal Seizures?
    Sufang Lin, Jianxiang Liao, Xia Zhao, Yan Hu, Li Chen, Yan Chen, Guosheng Liu, Yi Yao, Qiru Su, Ingrid E Scheffer, Feiqiu Wen.
      We evaluated the efficacy and safety of vigabatrin in focal epilepsy associated with tuberous sclerosis complex by retrospectively reviewing patients with focal epilepsy and tuberous sclerosis complex treated with vigabatrin at a pediatric epilepsy center over an 8-year period. Of 85 patients, 20 (23.5%) were seizure-free for >12 months, 45 (52.9%) were responders (≥50% seizure reduction), and 20 (23.5%) were nonresponders. The median age (in months) at seizure onset in the seizure-free group (median, 15; interquartile range [IQR], 6-23.3) was higher than that of responders (median, 5; IQR, 3-14) and nonresponders (median, 6; IQR, 2-12). Fewer patients in the seizure-free group had calcification in their largest tubers, but the presence of tuber calcification did not differ among groups. Vigabatrin is more likely to result in seizure freedom in children with tuberous sclerosis complex who have later infantile onset of focal seizures and no calcification in their largest tuber.
    Keywords:  child; focal seizures; tuber calcification; tuberous sclerosis complex; vigabatrin
    DOI:  https://doi.org/10.1177/08830738211048326
  2. AJNR Am J Neuroradiol. 2022 Mar 24.
    Prenatal MR Imaging Phenotype of Fetuses with Tuberous Sclerosis: An Institutional Case Series and Literature Review.
    S K Goergen, M C Fahey.
       BACKGROUND AND PURPOSE: Most patients with tuberous sclerosis complex (TSC) do not receive prenatal diagnosis. Our aim was to describe MR imaging findings to determine the following: 1. Whether normal fetal MR imaging is more common in fetuses imaged at ≤24 weeks' gestation compared with >24 weeks 2. The frequency of cardiac rhabdomyoma 3. The range of MR imaging phenotypes in fetal tuberous sclerosis complex.
    MATERIALS AND METHODS: Our institutional fetal MR imaging data base was searched between January 1, 2011 and June 30, 2021, for cases of TSC confirmed either by genetic testing, postnatal imaging, postmortem examination, or composite prenatal imaging findings and family history. A MEDLINE search was performed on June 8, 2021.
    RESULTS: Forty-seven published cases and 4 of our own cases were identified. Normal findings on fetal MR imaging were seen at a lower gestational age (mean, 24.7 [SD, 4.5 ] weeks) than abnormal findings on MR imaging (mean, 30.0 [SD, 5.3] weeks) (P = .008). Nine of 42 patients with abnormal MR imaging findings were ≤24 weeks' gestation. Subependymal nodules were present in 26/45 cases (57.8%), and cortical/subcortical lesions, in 17/46 (37.0%). A foramen of Monro nodule was present in 15 cases; in 2/7 cases in which this was unilateral, it was the only abnormal cerebral finding. Cardiac rhabdomyoma was absent in 3/48 cases at the time of fetal MR imaging but was discovered later. Megalencephaly or hemimegalencephaly was observed in 3 cases.
    CONCLUSIONS: Fetuses with abnormal cranial MR imaging findings were older than those with negative findings. Fetal hemimegalencephaly and megalencephaly should prompt fetal echocardiography. Cardiac rhabdomyoma was not always present at the time of fetal MR imaging.
    DOI:  https://doi.org/10.3174/ajnr.A7455
  3. BMJ Case Rep. 2022 Mar 24. pii: e244915. [Epub ahead of print]15(3):
    Neonatal rhabdomyoma with cardiac dysfunction: favourable response to sirolimus.
    Menghao Duan, Sreekanthan Sundararaghavan, Ai Ling Koh, Shui Yen Soh.
      Cardiac rhabdomyoma is the most common cardiac tumour in childhood, with a strong genetic association to tuberous sclerosis complex. Although most of the patients remain asymptomatic, a small proportion present with cardiac complications in the early neonatal period. Timely initiation of treatment can potentially reduce disease morbidity, and mammalian target of rapamycin (M-TOR) inhibitors play an effective role in promoting regression of these tumours. A healthy term newborn was diagnosed with a giant congenital cardiac rhabdomyoma at birth. He developed clinical signs of compromised cardiac function and progressive myocardial ischaemia, with echocardiography showing significant dyskinesia. He was treated with M-TOR inhibitors and clinical response was monitored via serial echocardiography. Remarkable regression of the tumour was visibly demonstrated within 4 months of sirolimus treatment. The infant continues to be reviewed by a multidisciplinary team of physicians and monitored for features of tuberous sclerosis complex.
    Keywords:  cardiovascular medicine; genetics; paediatric oncology; paediatrics (drugs and medicines)
    DOI:  https://doi.org/10.1136/bcr-2021-244915
  4. Aging (Albany NY). 2022 Mar 19. 14(undefined):
    Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice.
    Xiaofang Shi, S Joseph Endicott, Richard A Miller.
      Downregulation of mTOR (mechanistic target of rapamycin) can extend lifespan in multiple species, including mice. Growth hormone receptor knockout mice (GHRKO) and Snell dwarf mice have 40% or greater lifespan increase, and have lower mTORC1 function, which might reflect alteration in mTORC1 components or alteration of upstream proteins that modulate mTOR activity. Here we report reduction of mTORC components DEPTOR and PRAS40 in liver of these long-lived mice; these changes are opposite in direction to those that would be expected to lead to lower mTORC1 function. In contrast, levels of the upstream regulators TSC1 and TSC2 are elevated in GHRKO and Snell liver, kidney and skeletal muscle, and the ratio of phosphorylated TSC2 to total TSC2 is lower in the tissues of the long-lived mutant mice. In addition, knocking down TSC2 in GHRKO fibroblasts reversed the effects of the GHRKO mutation on mTORC1 function. Thus increased amounts of unphosphorylated, active, inhibitory TSC may contribute to lower mTORC1 function in these mice.
    Keywords:  TSC; aging; growth hormone receptor; lifespan extension; mTOR
    DOI:  https://doi.org/10.18632/aging.203959
  5. Ann Thorac Surg. 2022 Mar 16. pii: S0003-4975(22)00343-5. [Epub ahead of print]
    Multiple Interventions to Thoracoabdominal Aortic Aneurysm in a Child with Tuberous Sclerosis.
    Alejandro Olvera, Joseph M Besho, Akiko Tanaka, Hazim J Safi, Anthony L Estrera.
      Thoracoabdominal aortic aneurysms in toddlers are extremely rare. However, we experienced an extent III thoracoabdominal aortic aneurysm in a male with tuberous sclerosis, who underwent three open repairs and one endovascular aortic repair between the age of 4 and 18. This case highlights the potential for severe recurrent vascular aneurysms in the thoracic and abdominal aorta as a complication of tuberous sclerosis in children. Although aortic aneurysms in children are rare, it is vital to recognize these cases to prevent death due to rupture.
    Keywords:  Thoracoabdominal aortic aneurysm; toddler; tuberous sclerosis
    DOI:  https://doi.org/10.1016/j.athoracsur.2022.03.002
  6. Cell Rep. 2022 Mar 22. pii: S2211-1247(22)00307-2. [Epub ahead of print]38(12): 110563
    Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning.
    Katelyn N Benthall, Katherine R Cording, Alexander H C W Agopyan-Miu, Corinna D Wong, Emily Y Chen, Helen S Bateup.
      
    DOI:  https://doi.org/10.1016/j.celrep.2022.110563
  7. BMB Rep. 2022 Mar 24. pii: 5583. [Epub ahead of print]
    Effects of mTORC1 inhibition on proteasome activity and levels.
    Seo Hyeong Park, Won Hoon Choi, Min Jae Lee.
      The mechanistic target of rapamycin (mTOR) regulates numerous extracellular and intracellular signals involved in the maintenance of cellular homeostasis and cell growth. mTOR also functions as an endogenous inhibitor of autophagy. Under nutrient-rich conditions, mTOR complex 1 (mTORC1) phosphorylates the ULK1 complex, preventing its activation and subsequent autophagosome formation, while inhibition of mTORC1 using either rapamycin or nutrient deprivation induces autophagy. Autophagy and proteasomal proteolysis provide amino acids necessary for protein translation. Although the connection between mTORC1 and autophagy is well characterized, the association of mTORC1 inhibition with proteasome biogenesis and activity has not been fully elucidated yet. Proteasomes are long-lived cellular organelles. Their spatiotemporal rather than homeostatic regulation could be another adaptive cellular mechanism to respond to starvation. Here, we reviewed several published reports and the latest research from our group to examine the connection between mTORC1 and proteasome. We have also investigated and described the effect of mTORC1 inhibition on proteasome activity using purified proteasomes. Since mTORC1 inhibitors are currently evaluated as treatments for several human diseases, a better understanding of the link between mTORC1 activity and proteasome function is of utmost importance.
  8. Cancers (Basel). 2022 Mar 18. pii: 1555. [Epub ahead of print]14(6):
    Emerging Roles for Mammalian Target of Rapamycin (mTOR) Complexes in Bladder Cancer Progression and Therapy.
    Jianya Huan, Petros Grivas, Jasmine Birch, Donna E Hansel.
      The mammalian target of rapamycin (mTOR) pathway regulates important cellular functions. Aberrant activation of this pathway, either through upstream activation by growth factors, loss of inhibitory controls, or molecular alterations, can enhance cancer growth and progression. Bladder cancer shows high levels of mTOR activity in approximately 70% of urothelial carcinomas, suggesting a key role for this pathway in this cancer. mTOR signaling initiates through upstream activation of phosphatidylinositol 3 kinase (PI3K) and protein kinase B (AKT) and results in activation of either mTOR complex 1 (mTORC1) or mTOR complex 2 (mTORC2). While these complexes share several key protein components, unique differences in their complex composition dramatically alter the function and downstream cellular targets of mTOR activity. While significant work has gone into analysis of molecular alterations of the mTOR pathway in bladder cancer, this has not yielded significant benefit in mTOR-targeted therapy approaches in urothelial carcinoma to date. New discoveries regarding signaling convergence onto mTOR complexes in bladder cancer could yield unique insights the biology and targeting of this aggressive disease. In this review, we highlight the functional significance of mTOR signaling in urothelial carcinoma and its potential impact on future therapy implications.
    Keywords:  bladder cancer; inhibitor; invasion; mTOR; progression; targeted therapy; urothelial carcinoma
    DOI:  https://doi.org/10.3390/cancers14061555
  9. Nat Commun. 2022 Mar 22. 13(1): 1548
    S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions.
    Qiwei Jiang, Xiaomei Zhang, Xiaoming Dai, Shiyao Han, Xueji Wu, Lei Wang, Wenyi Wei, Ning Zhang, Wei Xie, Jianping Guo.
      Functioning as a master kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1) plays a fundamental role in phosphorylating and activating protein kinases A, B and C (AGC) family kinases, including AKT. However, upstream regulation of PDK1 remains largely elusive. Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT. Mechanistically, S6K1-mediated phosphorylation of PDK1 augments its interaction with 14-3-3 adaptor protein and homo-dimerization, subsequently dissociating PDK1 from phosphatidylinositol 3,4,5 triphosphate (PIP3) and retarding its interaction with AKT. Pathologically, tumor patient-associated PDK1 mutations, either attenuating S6K1-mediated PDK1 phosphorylation or impairing PDK1 interaction with 14-3-3, result in elevated AKT kinase activity and oncogenic functions. Taken together, our findings not only unravel a delicate feedback regulation of AKT signaling via S6K1-mediated PDK1 phosphorylation, but also highlight the potential strategy to combat mutant PDK1-driven cancers.
    DOI:  https://doi.org/10.1038/s41467-022-28910-8
  10. Dev Cell. 2022 Mar 15. pii: S1534-5807(22)00126-5. [Epub ahead of print]
    The central moTOR of metabolism.
    Judith Simcox, Dudley W Lamming.
      The protein kinase mechanistic target of rapamycin (mTOR) functions as a central regulator of metabolism, integrating diverse nutritional and hormonal cues to control anabolic processes, organismal physiology, and even aging. This review discusses the current state of knowledge regarding the regulation of mTOR signaling and the metabolic regulation of the four macromolecular building blocks of the cell: carbohydrate, nucleic acid, lipid, and protein by mTOR. We review the role of mTOR in the control of organismal physiology and aging through its action in key tissues and discuss the potential for clinical translation of mTOR inhibition for the treatment and prevention of diseases of aging.
    Keywords:  amino acids; lipids; mTOR; mTORC1; mTORC2; metabolism; protein; rapamycin
    DOI:  https://doi.org/10.1016/j.devcel.2022.02.024
  11. ACS Pharmacol Transl Sci. 2022 Mar 11. 5(3): 149-155
    Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy.
    Tianyi Wang, Kaiqi Long, Yang Zhou, Xiaoding Jiang, Jinzhao Liu, John H C Fong, Alan S L Wong, Wai-Lung Ng, Weiping Wang.
      As an important regulator of cell metabolism, proliferation, and survival, mTOR (mammalian target of rapamycin) signaling provides both a potential target for cancer treatment and a research tool for investigation of cell metabolism. One inhibitor for both mTORC1 and mTORC2 pathways, OSI-027, exhibited robust anticancer efficacy but induced side effects. Herein, we designed a photoactivatable OSI-027 prodrug, which allowed the release of OSI-027 after light irradiation to inhibit the mTOR signaling pathway, triggering autophagy and leading to cell death. This photoactivatable prodrug can provide novel strategies for mTOR-targeting cancer therapy and act as a new tool for investigating mTOR signaling and its related biological processes.
    DOI:  https://doi.org/10.1021/acsptsci.1c00230
  12. Neuroscience. 2022 Mar 16. pii: S0306-4522(22)00128-2. [Epub ahead of print]
    Rapamycin Pretreatment Attenuates High Glucose-induced Alteration of Synaptic Transmission in Hippocampal Dentate Gyrus Neurons.
    Tianyue Jiang, Wenxin Zhang, Yue Wang, Tao Zhang, Haiyun Wang, Zhuo Yang.
      Diabetic neuropathy is one of the most common complications in patients with diabetes and leads to cognitive impairment. It is suggested that protracted hyperglycemia is the main trigger of cognitive deficits in diabetes and causes hippocampal abnormalities. Rapamycin, an inhibitor of mammalian target of rapamycin complex 1 (mTORC1), can significantly ameliorate cognitive deficits in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and Huntington disease. We employed whole-cell patch clamping to examine the effects of rapamycin on neuronal electrophysiological characteristics of the hippocampal dentate gyrus under the condition of high glucose. We recorded the action potentials (APs) and the miniature excitatory postsynaptic currents (mEPSCs) of dentate gyrus neurons. We found that high glucose increased the half-width, the duration and decreased the peak amplitude of Aps as well as the inter-event interval (IEI) of mEPSCs in hippocampal dentate gyrus neurons. However, rapamycin pre-treatment reversed the changes induced by high glucose. Moreover, we demonstrated that rapamycin pre-treatment reversed the down-regulation of postsynaptic density protein 95 (PSD-95) expression caused by high glucose. Therefore, pre-treatment with rapamycin could ameliorate high glucose-induced alteration of synaptic transmission in the hippocampal dentate gyrus.
    Keywords:  AP; PSD-95; high glucose; mEPSCs; rapamycin
    DOI:  https://doi.org/10.1016/j.neuroscience.2022.03.012
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