bims-tubesc 2022-07-17 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2022–07–17
eight papers selected by

mTORC1 Crosstalk With Stress Granules in Aging and Age-Related Diseases.
The Multifaceted Role of Nutrient Sensing and mTORC1 Signaling in Physiology and Aging.
Defining the Magnetic Resonance Features of Renal Lesions and Their Response to Everolimus in a Transgenic Mouse Model of Tuberous Sclerosis Complex.
Blocking the Farnesyl Pocket of PDEδ Reduces Rheb-Dependent mTORC1 Activation and Survival of Tsc2-Null Cells.
MR Imaging Detection of CNS Lesions in Tuberous Sclerosis Complex: The Usefulness of T1WI with Chemical Shift Selective Images.
Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis.
Peripartum management of tuberous sclerosis complex complicated by massive angiomyolipomas.
Structure of the nutrient-sensing hub GATOR2.

Front Aging. 2021 ;2 761333

mTORC1 Crosstalk With Stress Granules in Aging and Age-Related Diseases.

Marti Cadena Sandoval, Alexander Martin Heberle, Ulrike Rehbein, Cecilia Barile, José Miguel Ramos Pittol, Kathrin Thedieck.

  The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a master regulator of metabolism and aging. A complex signaling network converges on mTORC1 and integrates growth factor, nutrient and stress signals. Aging is a dynamic process characterized by declining cellular survival, renewal, and fertility. Stressors elicited by aging hallmarks such as mitochondrial malfunction, loss of proteostasis, genomic instability and telomere shortening impinge on mTORC1 thereby contributing to age-related processes. Stress granules (SGs) constitute a cytoplasmic non-membranous compartment formed by RNA-protein aggregates, which control RNA metabolism, signaling, and survival under stress. Increasing evidence reveals complex crosstalk between the mTORC1 network and SGs. In this review, we cover stressors elicited by aging hallmarks that impinge on mTORC1 and SGs. We discuss their interplay, and we highlight possible links in the context of aging and age-related diseases.

Keywords:  MTOR; aging hallmarks; amino acids; autophagy; cellular signaling; insulin; stress; stress granules (SGs)

DOI:  https://doi.org/10.3389/fragi.2021.761333
Front Aging. 2021 ;2 707372

The Multifaceted Role of Nutrient Sensing and mTORC1 Signaling in Physiology and Aging.

Stephanie A Fernandes, Constantinos Demetriades.

  The mechanistic Target of Rapamycin (mTOR) is a growth-related kinase that, in the context of the mTOR complex 1 (mTORC1), touches upon most fundamental cellular processes. Consequently, its activity is a critical determinant for cellular and organismal physiology, while its dysregulation is commonly linked to human aging and age-related disease. Presumably the most important stimulus that regulates mTORC1 activity is nutrient sufficiency, whereby amino acids play a predominant role. In fact, mTORC1 functions as a molecular sensor for amino acids, linking the cellular demand to the nutritional supply. Notably, dietary restriction (DR), a nutritional regimen that has been shown to extend lifespan and improve healthspan in a broad spectrum of organisms, works via limiting nutrient uptake and changes in mTORC1 activity. Furthermore, pharmacological inhibition of mTORC1, using rapamycin or its analogs (rapalogs), can mimic the pro-longevity effects of DR. Conversely, nutritional amino acid overload has been tightly linked to aging and diseases, such as cancer, type 2 diabetes and obesity. Similar effects can also be recapitulated by mutations in upstream mTORC1 regulators, thus establishing a tight connection between mTORC1 signaling and aging. Although the role of growth factor signaling upstream of mTORC1 in aging has been investigated extensively, the involvement of signaling components participating in the nutrient sensing branch is less well understood. In this review, we provide a comprehensive overview of the molecular and cellular mechanisms that signal nutrient availability to mTORC1, and summarize the role that nutrients, nutrient sensors, and other components of the nutrient sensing machinery play in cellular and organismal aging.

Keywords:  aging; amino acids; dietary restriction; mTORC1; nutrient sensing

DOI:  https://doi.org/10.3389/fragi.2021.707372
Front Oncol. 2022 ;12 851192

Defining the Magnetic Resonance Features of Renal Lesions and Their Response to Everolimus in a Transgenic Mouse Model of Tuberous Sclerosis Complex.

Shubhangi Agarwal, Emilie Decavel-Bueff, Yung-Hua Wang, Hecong Qin, Romelyn Delos Santos, Michael J Evans, Renuka Sriram.

  Tuberous sclerosis complex (TSC) is an inherited genetic disorder characterized by mutations in TSC1 or TSC2 class of tumor suppressers which impact several organs including the kidney. The renal manifestations are usually in the form of angiomyolipoma (AML, in 80% of the cases) and cystadenomas. mTOR inhibitors such as rapamycin and everolimus have shown efficacy in reducing the renal tumor burden. Early treatment prevents the progression of AML; however, the tumors regrow upon cessation of therapy implying a lifelong need for monitoring and management of this morbid disease. There is a critical need for development of imaging strategies to monitor response to therapy and progression of disease which will also facilitate development of newer targeted therapy. In this study we evaluated the potential of multiparametric 1H magnetic resonance imaging (mpMRI) to monitor tumor response to therapy in a preclinical model of TSC, the transgenic mouse A/J Tsc2+/- . We found 2-dimensional T2-weighted sequence with 0.5 mm slice thickness to be optimal for detecting renal lesions as small as 0.016 mm3. Baseline characterization of lesions with MRI to assess physiological parameters such as cellularity and perfusion is critical for distinguishing between cystic and solid lesions. Everolimus treatment for three weeks maintained tumor growth at 36% from baseline, while control tumors displayed steady growth and were 70% larger than baseline at the end of therapy. Apparent diffusion coefficient, T1 values and normalized T2 intensity changes were also indictive of response to treatment. Our results indicate that standardization and implementation of improved MR imaging protocols will significantly enhance the utility of mpMRI in determining the severity and composition of renal lesions for better treatment planning.

Keywords:  AML; MRI; TSC; everolimus; kidney; mTOR; mp-MRI

DOI:  https://doi.org/10.3389/fonc.2022.851192
Front Pharmacol. 2022 ;13 912688

Blocking the Farnesyl Pocket of PDEδ Reduces Rheb-Dependent mTORC1 Activation and Survival of Tsc2-Null Cells.

Marisol Estrella Armijo, Emilia Escalona, Daniela Peña, Alejandro Farias, Violeta Morin, Matthias Baumann, Bert Matthias Klebl, Roxana Pincheira, Ariel Fernando Castro.

  Rheb is a small GTPase member of the Ras superfamily and an activator of mTORC1, a protein complex master regulator of cell metabolism, growth, and proliferation. Rheb/mTORC1 pathway is hyperactivated in proliferative diseases, such as Tuberous Sclerosis Complex syndrome and cancer. Therefore, targeting Rheb-dependent signaling is a rational strategy for developing new drug therapies. Rheb activates mTORC1 in the cytosolic surface of lysosomal membranes. Rheb's farnesylation allows its anchorage on membranes, while its proper localization depends on the prenyl-binding chaperone PDEδ. Recently, the use of PDEδ inhibitors has been proposed as anticancer agents because they interrupted KRas signaling leading to antiproliferative effects in KRas-dependent pancreatic cancer cells. However, the effect of PDEδ inhibition on the Rheb/mTORC1 pathway has been poorly investigated. Here, we evaluated the impact of a new PDEδ inhibitor, called Deltasonamide 1, in Tsc2-null MEFs, a Rheb-dependent overactivated mTORC1 cell line. By using a yeast two-hybrid assay, we first validated that Deltasonamide 1 disrupts Rheb-PDEδ interaction. Accordingly, we found that Deltasonamide 1 reduces mTORC1 targets activation. In addition, our results showed that Deltasonamide 1 has antiproliferative and cytotoxic effects on Tsc2-null MEFs but has less effect on Tsc2-wild type MEFs viability. This work proposes the pharmacological PDEδ inhibition as a new approach to target the abnormal Rheb/mTORC1 activation in Tuberous Sclerosis Complex cells.

Keywords:  Deltasonamide 1; PDEδ inhibitor; Rheb; Tsc2-null cells; mTORC1 signaling

DOI:  https://doi.org/10.3389/fphar.2022.912688
AJNR Am J Neuroradiol. 2022 Jul 14.

MR Imaging Detection of CNS Lesions in Tuberous Sclerosis Complex: The Usefulness of T1WI with Chemical Shift Selective Images.

H Fujii, N Sato, Y Kimura, M Mizutani, M Kusama, N Sumitomo, E Chiba, Y Shigemoto, M Takao, Y Takayama, M Iwasaki, E Nakagawa, H Mori.

BACKGROUND AND PURPOSE: CNS lesions of tuberous sclerosis complex are diagnosed mainly by T2WI, FLAIR, and sometimes T1WI with magnetization transfer contrast. The usefulness of T1WI with chemical shift selective images was recently reported in focal cortical dysplasia type IIb, which has histopathologic and imaging features similar to those of tuberous sclerosis complex. We investigated the usefulness of the T1WI with chemical shift selective images in detecting CNS lesions of tuberous sclerosis complex.
MATERIALS AND METHODS: We retrospectively reviewed 25 consecutive patients with tuberous sclerosis complex (mean age, 11.9 [SD, 8.9] years; 14 males) who underwent MR imaging including T1WI, T1WI with magnetization transfer contrast, T1WI with chemical shift selective, T2WI, and FLAIR images. Two neuroradiologists assessed the number of CNS lesions in each sequence and compared them in 2 steps: among T1WI, T1WI with magnetization transfer contrast and T1WI with chemical shift selective images, and among T2WI, FLAIR, and T1WI with chemical shift selective images. We calculated the contrast ratio of the cortical tubers and of adjacent normal-appearing gray matter and the contrast ratio of radial migration lines and adjacent normal-appearing white matter in each sequence and compared them.
RESULTS: T1WI with chemical shift selective images was significantly superior to T1WI with magnetization transfer contrast for the detection of radial migration lines and contrast ratio of radial migration lines. There was no significant difference between T1WI with chemical shift selective images and T1WI with magnetization transfer contrast for the detection of cortical tubers and the contrast ratio of the cortical tubers. Both T2WI and FLAIR were statistically superior to T1WI with chemical shift selective images for the detection of cortical tubers. T1WI with chemical shift selective images was significantly superior to T2WI and FLAIR for the detection of radial migration lines.
CONCLUSIONS: The usefulness of T1WI with chemical shift selective images in detecting radial migration lines was demonstrated. Our findings suggest that the combination of T1WI with chemical shift selective images, T2WI, and FLAIR would be useful to evaluate the CNS lesions of patients with tuberous sclerosis complex in daily clinical practice.

DOI: https://doi.org/10.3174/ajnr.A7573
Nat Commun. 2022 Jul 15. 13(1): 4107

Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis.

Gloria Ursino, Giorgio Ramadori, Anna Höfler, Soline Odouard, Pryscila D S Teixeira, Florian Visentin, Christelle Veyrat-Durebex, Giulia Lucibello, Raquel Firnkes, Serena Ricci, Claudia R Vianna, Lin Jia, Mirjam Dirlewanger, Philippe Klee, Joel K Elmquist, Johannes Roth, Thomas Vogl, Valérie M Schwitzgebel, François R Jornayvaz, Andreas Boland, Roberto Coppari.

Unrestrained ketogenesis leads to life-threatening ketoacidosis whose incidence is high in patients with diabetes. While insulin therapy reduces ketogenesis this approach is sub-optimal. Here, we report an insulin-independent pathway able to normalize diabetic ketogenesis. By generating insulin deficient male mice lacking or re-expressing Toll-Like Receptor 4 (TLR4) only in liver or hepatocytes, we demonstrate that hepatic TLR4 in non-parenchymal cells mediates the ketogenesis-suppressing action of S100A9. Mechanistically, S100A9 acts extracellularly to activate the mechanistic target of rapamycin complex 1 (mTORC1) in a TLR4-dependent manner. Accordingly, hepatic-restricted but not hepatocyte-restricted loss of Tuberous Sclerosis Complex 1 (TSC1, an mTORC1 inhibitor) corrects insulin-deficiency-induced hyperketonemia. Therapeutically, recombinant S100A9 administration restrains ketogenesis and improves hyperglycemia without causing hypoglycemia in diabetic mice. Also, circulating S100A9 in patients with ketoacidosis is only marginally increased hence unveiling a window of opportunity to pharmacologically augment S100A9 for preventing unrestrained ketogenesis. In summary, our findings reveal the hepatic S100A9-TLR4-mTORC1 axis in non-parenchymal cells as a promising therapeutic target for restraining diabetic ketogenesis.

DOI: https://doi.org/10.1038/s41467-022-31803-5
Anaesth Rep. 2022 Jul-Dec;10(2):10(2): e12176

Peripartum management of tuberous sclerosis complex complicated by massive angiomyolipomas.

C Knapp, M Ince, A Zacharzewski.

  Tuberous sclerosis complex is a genetic disease that can affect multiple organs, commonly the renal, central nervous, cardiac and respiratory systems. Here, we present the peripartum management of a woman with a new diagnosis of tuberous sclerosis complex associated with massive renal angiomyolipomas. There was significant risk of catastrophic haemorrhage from the angiomyolipomas during pregnancy. This created a challenging scenario for the anaesthetists, obstetricians, urologists and interventional radiologists involved in their care, necessitating collaborative working, numerous investigations and honest patient-centred discussions. Evidence for the management of tuberous sclerosis and angiomyolipomas in pregnancy does not appear to have been previously reported. After much consideration, arterial embolisation of the most vascular area of the angiomyolipoma was completed at 28 weeks gestation under remifentanil sedation. An elective caesarean section under combined spinal epidural anaesthesia was completed at 37 + 3 weeks gestation. Central nervous system involvement must always be considered; benign tumours within the brain and spinal cord may contraindicate neuraxial techniques. Early multidisciplinary involvement is essential due to the diverse and complex nature of tuberous sclerosis. Individuals differ in their presentation and disease severity; therefore, they must be assessed on an individual basis with management tailored accordingly.

Keywords:  pregnancy: haemodynamic effects; renal insufficiency: diagnosis; spinal anaesthesia: complications; surgery risk during pregnancy

DOI:  https://doi.org/10.1002/anr3.12176
Nature. 2022 Jul 13.

Structure of the nutrient-sensing hub GATOR2.

Max L Valenstein, Kacper B Rogala, Pranav V Lalgudi, Edward J Brignole, Xin Gu, Robert A Saxton, Lynne Chantranupong, Jonas Kolibius, Jan-Philipp Quast, David M Sabatini.

Mechanistic target of rapamycin complex 1 (mTORC1) controls growth by regulating anabolic and catabolic processes in response to environmental cues, including nutrients1,2. Amino acids signal to mTORC1 through the Rag GTPases, which are regulated by several protein complexes, including GATOR1 and GATOR2. GATOR2, which has five components (WDR24, MIOS, WDR59, SEH1L and SEC13), is required for amino acids to activate mTORC1 and interacts with the leucine and arginine sensors SESN2 and CASTOR1, respectively3-5. Despite this central role in nutrient sensing, GATOR2 remains mysterious as its subunit stoichiometry, biochemical function and structure are unknown. Here we used cryo-electron microscopy to determine the three-dimensional structure of the human GATOR2 complex. We found that GATOR2 adopts a large (1.1 MDa), two-fold symmetric, cage-like architecture, supported by an octagonal scaffold and decorated with eight pairs of WD40 β-propellers. The scaffold contains two WDR24, four MIOS and two WDR59 subunits circularized via two distinct types of junction involving non-catalytic RING domains and α-solenoids. Integration of SEH1L and SEC13 into the scaffold through β-propeller blade donation stabilizes the GATOR2 complex and reveals an evolutionary relationship to the nuclear pore and membrane-coating complexes6. The scaffold orients the WD40 β-propeller dimers, which mediate interactions with SESN2, CASTOR1 and GATOR1. Our work reveals the structure of an essential component of the nutrient-sensing machinery and provides a foundation for understanding the function of GATOR2 within the mTORC1 pathway.

DOI: https://doi.org/10.1038/s41586-022-04939-z