bims-tubesc 2021-12-26 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2021–12–26
thirteen papers selected by

Stop the Lights-Turning Off the Electricity in Tuberous Sclerosis.
Infantile Spasms in Tuberous Sclerosis Complex: Lesion or Network?
The importance of imaging in tuberous sclerosis complex (tsc) in children: Two cases.
Management of adult tuberous sclerosis complex-related angiomyolipoma: A single-center experience.
Differential Modulation of Matrix Metalloproteinases-2 and -7 in LAM/TSC Cells.
Atypical cutaneous presentation of tuberous sclerosis complex: Giant angiofibroma on the scalp.
Activation of Downstream mTORC1 Target Ribosomal Protein S6 Kinase (S6K) Can Be Found in a Subgroup of Dutch Patients with Granulomatous Pulmonary Disease.
Indoxyl Sulfate Contributes to mTORC1-Induced Renal Fibrosis via The OAT/NADPH Oxidase/ROS Pathway.
The Bumpy Road towards mTOR Inhibition in Glioblastoma: Quo Vadis?
New Insights in Paediatric Dermatopathology.
RalA, PLD and mTORC1 Are Required for Kinase-Independent Pathways in DGKβ-Induced Neurite Outgrowth.
Cross-talk between LAM cells and fibroblasts may influence alveolar epithelial cell behavior in Lymphangioleiomyomatosis.
Differential effects of mTOR inhibition and dietary ketosis in a mouse model of subacute necrotizing encephalomyelopathy.

Epilepsy Curr. 2021 Oct;21(5): 346-348

Stop the Lights-Turning Off the Electricity in Tuberous Sclerosis.

Peter Widdess-Walsh.



Keywords:  antiepileptic; electroencephalography; epilepsy; prevention; tuberous sclerosis; vigabatrin

DOI:  https://doi.org/10.1177/15357597211031075
Epilepsy Curr. 2021 Oct;21(5): 349-350

Infantile Spasms in Tuberous Sclerosis Complex: Lesion or Network?

Charuta Joshi, Joshua J Bear.

DOI: https://doi.org/10.1177/15357597211026405
Radiol Case Rep. 2022 Feb;17(2): 399-403

The importance of imaging in tuberous sclerosis complex (tsc) in children: Two cases.

Kreshnike Dedushi, Fjolla Hyseni, Juna Musa, Kristi Saliaj, Valon Vokshi, Ali Guy, Atiq Bhatti, Muhammad Tahir, Jeton Shatri, Bardha Dervishi, Krenare Shabani, Mentor Shatri.

  Tuberous sclerosis complex (TSC) is an inherited, multisystemic, hamartomatous neurocutaneous disorder, with an autosomal dominant inheritance pattern. It affects multiple organs, however the most susceptible ones include the brain, skin, kidneys, lungs, the retina, and the heart. TSC is characterized by considerable clinical heterogeneity. The majority of patients present with a constellation of clinical signs and symptoms, most prominently central nervous system manifestations including epilepsy, cognitive impairment and autism spectrum disorders, cutaneous, cardiac, renal and ophthalmic manifestations. Epilepsy affects 70% - 90% of patients, representing the primary neurological feature and 1 of the foremost clinical findings of the disorder. Cardiac rhabdomyomas are the most frequent cardiac manifestations, appearing as isolated or multiple lesions. Herein, we present 2 patients diagnosed with tuberous sclerosis. A 3-month-old male patient with cardiac rhabdomyomas and hypopigmented macules and a 19-month-old male patient with partial epilepsy and mild psychomotor retardation. As brain lesions represent some of the most prevalent clinical features and early onset seizures are associated with more severe cognitive, function delay, through this article we hope to emphasize the potential role MRI can play in the diagnostic workup of TSC, to ensure a more timely diagnosis, thus modifying the natural course of the disorder and its prognosis.

Keywords:  Epilepsy; Magnetic Resonance Imaging; Pediatrics; Rhabdomyoma; Tuberous sclerosis

DOI:  https://doi.org/10.1016/j.radcr.2021.11.007
Can Urol Assoc J. 2021 Dec 21.

Management of adult tuberous sclerosis complex-related angiomyolipoma: A single-center experience.

Terry Li, Meghna Siddoji, Jen Hoogenes, Camilla Tajzler, Nikhita Singhal, Anil Kapoor.

INTRODUCTION: Tuberous sclerosis complex (TSC) is a rare, multisystem, genetic disease. A significant cause of TSC-related morbidity is potential bleeding from renal angiomyolipoma (AML). To pre-emptively decrease AML bleeding, mTOR inhibitors can be used; however, thresholds for initiating and maintaining everolimus therapy remain uncertain. Recent literature suggests not triggering active treatment of AMLs based on size thresholds alone. We evaluated the appropriateness of initiating everolimus therapy in asymptomatic patients after considering AML size, rate of growth, and other factors.
METHODS: Diagnostic criteria developed by the 2012 International TSC Consensus Group and presence of AML were used as inclusion criteria. Medical and imaging reports of 20 TSC patients from a single center were reviewed.
RESULTS: Mean age was 40.55 (±16.27) and 11 patients were female. Eight asymptomatic patients at high risk for complications underwent everolimus therapy, of which seven (88%) demonstrated decreased AML size but multiple side effects were reported. Four high-risk asymptomatic patients did not undergo therapy due to side effect concerns, while four low-risk asymptomatic patients had stable AMLs under active surveillance. Four patients had reduced AMLs through local therapy.
CONCLUSIONS: Everolimus treatment was effective for managing AML size in most high-risk asymptomatic patients with tolerable side effects. AML size can remain relatively stable for asymptomatic low-risk patients despite not receiving intervention(s). Patients with TSC-related making including factors such as bleeding risk, AML growth rate, and number and absolute size of AMLs.

DOI: https://doi.org/10.5489/cuaj.7556
Biomedicines. 2021 Nov 24. pii: 1760. [Epub ahead of print]9(12):

Differential Modulation of Matrix Metalloproteinases-2 and -7 in LAM/TSC Cells.

Silvia Ancona, Emanuela Orpianesi, Clara Bernardelli, Eloisa Chiaramonte, Raffaella Chiaramonte, Silvia Terraneo, Fabiano Di Marco, Elena Lesma.

  Matrix metalloproteinase (MMP) dysregulation is implicated in several diseases, given their involvement in extracellular matrix degradation and cell motility. In lymphangioleiomyomatosis (LAM), a pulmonary rare disease, MMP-2 and MMP-9 have been detected at high levels in serum and urine. LAM cells, characterized by a mutation in the tuberous sclerosis complex (TSC)1 or TSC2, promote cystic lung destruction. The role of MMPs in invasive and destructive LAM cell capability has not yet been fully understood. We evaluated MMP-2 and MMP-7 expression, secretion, and activity in primary LAM/TSC cells that bear a TSC2 germline mutation and an epigenetic modification and depend on epidermal growth factor (EGF) for survival. 5-azacytidine restored tuberin expression with a reduction of MMP-2 and MMP-7 levels and inhibits motility, similarly to rapamycin and anti-EGFR antibody. Both drugs reduced MMP-2 and MMP-7 secretion and activity during wound healing and decreased their expression in lung nodules of a LAM mouse model. In LAM/TSC cells, MMP-2 and MMP-7 are dependent on tuberin expression, cellular adhesion, and migration. MMPs appears sensitive to rapamycin and anti-EGFR antibody only during cellular migration. Our data indicate a complex and differential modulation of MMP-2 and MMP-7 in LAM/TSC cells, likely critical for lung parenchyma remodeling during LAM progression.

Keywords:  LAM; MMP-2; MMP-7; TSC; cell motility

DOI:  https://doi.org/10.3390/biomedicines9121760
Arq Neuropsiquiatr. 2021 Dec 17. pii: S0004-282X2021005027202. [Epub ahead of print]

Atypical cutaneous presentation of tuberous sclerosis complex: Giant angiofibroma on the scalp.

Leonardo Furtado Freitas, Leomar Benicio Maia Segundo, Danilo Manuel Cerqueira Costa, Márcio Luís Duarte, Luís Antônio Tobaru Tibana.

DOI: https://doi.org/10.1590/0004-282X-ANP-2021-0315
Cells. 2021 Dec 15. pii: 3545. [Epub ahead of print]10(12):

Activation of Downstream mTORC1 Target Ribosomal Protein S6 Kinase (S6K) Can Be Found in a Subgroup of Dutch Patients with Granulomatous Pulmonary Disease.

Raisa Kraaijvanger, Kees Seldenrijk, Els Beijer, Jan Damen, Jayne Louise Wilson, Thomas Weichhart, Jan C Grutters, Marcel Veltkamp.

  Mechanistic target of rapamycin complex 1 (mTORC1) has been linked to different diseases. The mTORC1 signaling pathway is suggested to play a role in the granuloma formation of sarcoidosis. Recent studies demonstrated conflicting data on mTORC1 activation in patients with sarcoidosis by measuring activation of its downstream target S6 kinase (S6K) with either 33% or 100% of patients. Therefore, the aim of our study was to reevaluate the percentage of S6K activation in sarcoidosis patients in a Dutch cohort. To investigate whether this activation is specific for sarcoid granulomas, we also included Dutch patients with other granulomatous diseases of the lung. The activation of the S6K signaling pathway was evaluated by immunohistochemical staining of its downstream effector phospho-S6 in tissue sections. Active S6K signaling was detected in 32 (43%) of the sarcoidosis patients. Twelve (31%) of the patients with another granulomatous disorder also showed activated S6K signaling, demonstrating that the mTORC1 pathway may be activated in a range for different granulomatous diseases (p = 0.628). Activation of S6K can only be found in a subgroup of patients with sarcoidosis, as well as in patients with other granulomatous pulmonary diseases, such as hypersensitivity pneumonitis or vasculitis. No association between different clinical phenotypes and S6K activation can be found in sarcoidosis.

Keywords:  S6K; granuloma; mTORC1; phenotyping; sarcoidosis

DOI:  https://doi.org/10.3390/cells10123545
Toxins (Basel). 2021 Dec 18. pii: 909. [Epub ahead of print]13(12):

Indoxyl Sulfate Contributes to mTORC1-Induced Renal Fibrosis via The OAT/NADPH Oxidase/ROS Pathway.

Takehiro Nakano, Hiroshi Watanabe, Tadashi Imafuku, Kai Tokumaru, Issei Fujita, Nanaka Arimura, Hitoshi Maeda, Motoko Tanaka, Kazutaka Matsushita, Masafumi Fukagawa, Toru Maruyama.

  Activation of mTORC1 (mechanistic target of rapamycin complex 1) in renal tissue has been reported in chronic kidney disease (CKD)-induced renal fibrosis. However, the molecular mechanisms responsible for activating mTORC1 in CKD pathology are not well understood. The purpose of this study was to identify the uremic toxin involved in mTORC1-induced renal fibrosis. Among the seven protein-bound uremic toxins, only indoxyl sulfate (IS) caused significant activation of mTORC1 in human kidney 2 cells (HK-2 cells). This IS-induced mTORC1 activation was inhibited in the presence of an organic anion transporter inhibitor, a NADPH oxidase inhibitor, and an antioxidant. IS also induced epithelial-mesenchymal transition of tubular epithelial cells (HK-2 cells), differentiation of fibroblasts into myofibroblasts (NRK-49F cells), and inflammatory response of macrophages (THP-1 cells), which are associated with renal fibrosis, and these effects were inhibited in the presence of rapamycin (mTORC1 inhibitor). In in vivo experiments, IS overload was found to activate mTORC1 in the mouse kidney. The administration of AST-120 or rapamycin targeted to IS or mTORC1 ameliorated renal fibrosis in Adenine-induced CKD mice. The findings reported herein indicate that IS activates mTORC1, which then contributes to renal fibrosis. Therapeutic interventions targeting IS and mTORC1 could be effective against renal fibrosis in CKD.

Keywords:  AST-120; chronic kidney disease; indoxyl sulfate; mTORC1; renal fibrosis

DOI:  https://doi.org/10.3390/toxins13120909
Biomedicines. 2021 Dec 01. pii: 1809. [Epub ahead of print]9(12):

The Bumpy Road towards mTOR Inhibition in Glioblastoma: Quo Vadis?

Kostas A Papavassiliou, Athanasios G Papavassiliou.

  Glioblastoma multiforme (GBM), a grade IV astrocytoma, is a lethal brain tumor with a poor prognosis. Despite recent advances in the molecular biology of GBM, neuro-oncologists have very limited treatment options available to improve the survival of GBM patients. A prominent signaling pathway implicated in GBM pathogenesis is that of the mechanistic target of rapamycin (mTOR). Attempts to target the mTOR pathway with first-generation mTOR inhibitors appeared promising in the preclinical stage; however, results have been disappointing in clinical trials, owing to the heterogeneous nature of GBM, escape mechanisms against treatment, the blood-brain barrier, drug-related toxicities, and the imperfect design of clinical trials, among others. The development of next-generation mTOR inhibitors and their current evaluation in clinical trials have sparked new hope to realize the clinical potential of mTOR inhibitors in GBM. Meanwhile, studies are continuously furthering our understanding of mTOR signaling dysregulation, its downstream effects, and interplay with other signaling pathways in GBM tumors. Therefore, it remains to be seen whether targeting mTOR in GBM will eventually prove to be fruitful or futile.

Keywords:  glioblastoma multiforme; mTOR inhibitors; mTOR signaling; mTORC1; mTORC2

DOI:  https://doi.org/10.3390/biomedicines9121809
Dermatopathology (Basel). 2021 Dec 07. 8(4): 531-534

New Insights in Paediatric Dermatopathology.

Sylvie Fraitag.

  Paediatric dermatology is an expanding subspeciality [...].

Keywords:  auto-inflammatory disorders; bullous eruption in infancy; childhood melanoma; congenital cystic masses of the neck; congenital cysts; ichthyoses; infants; neonates; nodules; paediatric dermatopathology; panniculitis; pseudo-malignancy; subcutaneous spindle cell neoplasms; tuberous sclerosis complex; venous malformations

DOI:  https://doi.org/10.3390/dermatopathology8040056
Biomolecules. 2021 Dec 02. pii: 1814. [Epub ahead of print]11(12):

RalA, PLD and mTORC1 Are Required for Kinase-Independent Pathways in DGKβ-Induced Neurite Outgrowth.

Takuya Kano, Ryosuke Tsumagari, Akio Nakashima, Ushio Kikkawa, Shuji Ueda, Minoru Yamanoue, Nobuyuki Takei, Yasuhito Shirai.

  Diacylglycerol kinase β (DGKβ) is an enzyme that converts diacylglycerol to phosphatidic acid and is mainly expressed in the cerebral cortex, hippocampus and striatum. We previously reported that DGKβ induces neurite outgrowth and spinogenesis, contributing to higher brain functions, including emotion and memory. To elucidate the mechanisms involved in neuronal development by DGKβ, we investigated the importance of DGKβ activity in the induction of neurite outgrowth using human neuroblastoma SH-SY5Y cells. Interestingly, both wild-type DGKβ and the kinase-negative (KN) mutant partially induced neurite outgrowth, and these functions shared a common pathway via the activation of mammalian target of rapamycin complex 1 (mTORC1). In addition, we found that DGKβ interacted with the small GTPase RalA and that siRNA against RalA and phospholipase D (PLD) inhibitor treatments abolished DGKβKN-induced neurite outgrowth. These results indicate that binding of RalA and activation of PLD and mTORC1 are involved in DGKβKN-induced neurite outgrowth. Taken together with our previous reports, mTORC1 is a key molecule in both kinase-dependent and kinase-independent pathways of DGKβ-mediated neurite outgrowth, which is important for higher brain functions.

Keywords:  RalA; diacylglycerol kinase; mammalian target of rapamycin; neurite; phosphatidic acid; phospholipase D (PLD)

DOI:  https://doi.org/10.3390/biom11121814
Am J Physiol Lung Cell Mol Physiol. 2021 Dec 22.

Cross-talk between LAM cells and fibroblasts may influence alveolar epithelial cell behavior in Lymphangioleiomyomatosis.

Debbie Clements, Suzanne Miller, Roya Babaei-Jadidi, Mike Adam, S Steven Potter, Simon R Johnson.

  Lymphangioleiomyomatosis (LAM) is a female specific cystic lung disease in which TSC2 deficient LAM cells, LAM-Associated Fibroblasts (LAFs) and other cell types infiltrate the lungs. LAM lesions can be associated with type II alveolar epithelial cells (AT2 cells). We hypothesised that the behaviour of AT2 cells in LAM is influenced locally by LAFs. We tested this hypothesis in patient samples and in vitro. In human LAM lung, nodular AT2 cells show enhanced proliferation when compared to parenchymal AT2 cells, demonstrated by increased Ki67 expression. Further, nodular AT2 cells express proteins associated with epithelial activation in other disease states including Matrix Metalloproteinase 7, and Fibroblast Growth Factor 7 (FGF7). In vitro, LAF conditioned medium is mitogenic and positively chemotactic for epithelial cells, increases the rate of epithelial repair and protects against apoptosis. In vitro, LAM patient-derived TSC2 null cells cocultured with LAFs upregulate LAF expression of the epithelial chemokine and mitogen FGF7, which is a potential mediator of fibroblast-epithelial crosstalk, in an mTOR dependent manner. In a novel in vitro model of LAM, ex vivo cultured LAM lung-derived microtissues promote both epithelial migration and adhesion. Our findings suggest that AT2 cells in LAM display a proliferative, activated phenotype and that fibroblast accumulation following LAM cell infiltration into the parenchyma contributes to this change in AT2 cell behaviour. Fibroblast-derived FGF7 may contribute to the cross-talk between LAFs and hyperplastic epithelium in vivo, but does not appear to be the main driver of the effects of LAFs on epithelial cells in vitro.

Keywords:  Epithelium; FGF7; Fibroblasts; Lymphangioleiomyomatosis

DOI:  https://doi.org/10.1152/ajplung.00351.2021
Neurobiol Dis. 2021 Dec 20. pii: S0969-9961(21)00343-0. [Epub ahead of print]163 105594

Differential effects of mTOR inhibition and dietary ketosis in a mouse model of subacute necrotizing encephalomyelopathy.

Rebecca Bornstein, Katerina James, Julia Stokes, Kyung Yeon Park, Ernst-Bernhard Kayser, John Snell, Angela Bard, Yihan Chen, Franck Kalume, Simon C Johnson.

  Genetic mitochondrial diseases are the most frequent cause of inherited metabolic disorders and one of the most prevalent causes of heritable neurological disease. Leigh syndrome is the most common clinical presentation of pediatric mitochondrial disease, typically appearing in the first few years of life, and involving severe multisystem pathologies. Clinical care for Leigh syndrome patients is difficult, complicated by the wide range of symptoms including characteristic progressive CNS lesion, metabolic sequelae, and epileptic seizures, which can be intractable to standard management. While no proven therapies yet exist for the underlying mitochondrial disease, a ketogenic diet has led to some reports of success in managing mitochondrial epilepsies, with ketosis reducing seizure risk and severity. The impact of ketosis on other aspects of disease progression in Leigh syndrome has not been studied, however, and a rigorous study of the impact of ketosis on seizures in mitochondrial disease is lacking. Conversely, preclinical efforts have identified the intracellular nutrient signaling regulator mTOR as a promising therapeutic target, with data suggesting the benefits are mediated by metabolic changes. mTOR inhibition alleviates epilepsies arising from defects in TSC, an mTOR regulator, but the therapeutic potential of mTOR inhibition in seizures related to primary mitochondrial dysfunction is unknown. Given that ketogenic diet is used clinically in the setting of mitochondrial disease, and mTOR inhibition is in clinical trials for intractable pediatric epilepsies of diverse causal origins, a direct experimental assessment of their effects is imperative. Here, we define the impact of dietary ketosis on survival and CNS disease in the Ndufs4(KO) mouse model of Leigh syndrome and the therapeutic potential of both dietary ketosis and mTOR inhibition on seizures in this model. These data provide timely insight into two important clinical interventions.

Keywords:  Epilepsy; Ketogenic diet; Ketosis; Mitochondrial disease; Seizure; mTOR

DOI:  https://doi.org/10.1016/j.nbd.2021.105594