bims-tubesc 2021-10-17 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2021–10–17
ten papers selected by

Sporadic facial angiofibroma and sporadic angiomyolipoma mimicking tuberous sclerosis complex.
Epilepsy in the mTORopathies: opportunities for precision medicine.
Early Vocal Development in Tuberous Sclerosis Complex.
mTOR-dependent immunometabolism as Achilles' heel of anticancer therapy.
Tyrosine Phosphorylation of DEPTOR Functions as a Molecular Switch to Activate mTOR Signaling.
Perspective on mTOR-dependent Protection in Status Epilepticus.
[Renal carcinoma with leiomyomatous stroma and osseous metaplasia from a patient diagnosed with a tuberous sclerosis complex].
Incidental case finding of a 19-year-old woman with Tuberous Sclerosis Complex: A step-wise Multidisciplinary approach.
GluN2A-ERK-mTOR pathway confers a vulnerability to LPS-induced depressive-like behaviour.
Everolimus accelerates Erastin and RSL3-induced ferroptosis in renal cell carcinoma.

J Med Genet. 2021 Oct 11. pii: jmedgenet-2021-108160. [Epub ahead of print]

Sporadic facial angiofibroma and sporadic angiomyolipoma mimicking tuberous sclerosis complex.

Katarzyna Klonowska, Elizabeth A Thiele, Joannes M Grevelink, Aaron R Thorner, David J Kwiatkowski.

  Tuberous sclerosis complex (TSC) is a genetic syndrome due to mutations in either TSC1 or TSC2, leading to the development of hamartomatous tumours at multiple body sites, including facial skin (facial angiofibroma (FAF)), brain (cortical tubers) and kidney (angiomyolipoma (AML)). In this report, we describe an individual with minimal TSC clinical features, who had 'no mutation identified' (NMI) by prior genetic testing in a clinical laboratory. Our massively parallel sequencing (MPS) analysis of multiple samples from different body sites and tumours (including blood, saliva, normal skin, AML and FAF) revealed an extraordinary situation in which FAF and AML had completely independent inactivating biallelic variants in TSC2, not present in other matched samples. This suggests that the two different lesions (AML and FAF) are not due to the same underlying germline or mosaic mutation, rather both are likely sporadic events. This case demonstrates the relevance of thorough clinical examination, high-coverage MPS of multiple tumours and matched normal tissues, and appropriate genetic counselling for individuals with marginal TSC features and possible TSC1 or TSC2 mosaicism.

Keywords:  diagnosis; genetic counseling; genetics; mutation

DOI:  https://doi.org/10.1136/jmedgenet-2021-108160
Brain Commun. 2021 ;3(4): fcab222

Epilepsy in the mTORopathies: opportunities for precision medicine.

Patrick B Moloney, Gianpiero L Cavalleri, Norman Delanty.

  The mechanistic target of rapamycin signalling pathway serves as a ubiquitous regulator of cell metabolism, growth, proliferation and survival. The main cellular activity of the mechanistic target of rapamycin cascade funnels through mechanistic target of rapamycin complex 1, which is inhibited by rapamycin, a macrolide compound produced by the bacterium Streptomyces hygroscopicus. Pathogenic variants in genes encoding upstream regulators of mechanistic target of rapamycin complex 1 cause epilepsies and neurodevelopmental disorders. Tuberous sclerosis complex is a multisystem disorder caused by mutations in mechanistic target of rapamycin regulators TSC1 or TSC2, with prominent neurological manifestations including epilepsy, focal cortical dysplasia and neuropsychiatric disorders. Focal cortical dysplasia type II results from somatic brain mutations in mechanistic target of rapamycin pathway activators MTOR, AKT3, PIK3CA and RHEB and is a major cause of drug-resistant epilepsy. DEPDC5, NPRL2 and NPRL3 code for subunits of the GTPase-activating protein (GAP) activity towards Rags 1 complex (GATOR1), the principal amino acid-sensing regulator of mechanistic target of rapamycin complex 1. Germline pathogenic variants in GATOR1 genes cause non-lesional focal epilepsies and epilepsies associated with malformations of cortical development. Collectively, the mTORopathies are characterized by excessive mechanistic target of rapamycin pathway activation and drug-resistant epilepsy. In the first large-scale precision medicine trial in a genetically mediated epilepsy, everolimus (a synthetic analogue of rapamycin) was effective at reducing seizure frequency in people with tuberous sclerosis complex. Rapamycin reduced seizures in rodent models of DEPDC5-related epilepsy and focal cortical dysplasia type II. This review outlines a personalized medicine approach to the management of epilepsies in the mTORopathies. We advocate for early diagnostic sequencing of mechanistic target of rapamycin pathway genes in drug-resistant epilepsy, as identification of a pathogenic variant may point to an occult dysplasia in apparently non-lesional epilepsy or may uncover important prognostic information including, an increased risk of sudden unexpected death in epilepsy in the GATORopathies or favourable epilepsy surgery outcomes in focal cortical dysplasia type II due to somatic brain mutations. Lastly, we discuss the potential therapeutic application of mechanistic target of rapamycin inhibitors for drug-resistant seizures in GATOR1-related epilepsies and focal cortical dysplasia type II.

Keywords:  GATOR1-related epilepsies; everolimus; focal cortical dysplasia type II; the mTORopathies; tuberous sclerosis complex

DOI:  https://doi.org/10.1093/braincomms/fcab222
Pediatr Neurol. 2021 Sep 10. pii: S0887-8994(21)00184-3. [Epub ahead of print]125 48-52

Early Vocal Development in Tuberous Sclerosis Complex.

Tanjala T Gipson, Gordon Ramsay, Ellen E Ellison, Edina R Bene, Helen L Long, D Kimbrough Oller.

   BACKGROUND: Our goal was to assess for the first time early vocalizations as precursors to speech in audio-video recordings of infants with tuberous sclerosis complex (TSC).
METHODS: We randomly selected 40 infants with TSC from the TSC Autism Center of Excellence Research Network data set. Using human observers, we analyzed 74 audio-video recordings within a flexible software-based coding environment. During the recordings, infants were engaged in developmental testing. We determined syllables per minute (volubility), the number of consonant-vowel combinations, such as 'ba' (canonical babbling), and the canonical babbling ratio (canonical syllables/total syllables) and compared the data with 2 groups of typically developing (TD) infants. One comparison group's data had come from a laboratory setting, while the other's had come from all-day Language Environment Analysis recordings at home.
RESULTS: Compared with TD infants in laboratory and all-day Language Environment Analysis recordings, entry into the canonical babbling stage was delayed in the majority of infants with TSC, and the canonical babbling ratio was low (TD mean = 0.346, SE = 0.19; TSC mean = 0.117, SE = 0.023). Volubility level in infants with TSC was less than half that of TD infants (TD mean = 9.82, SE = 5.78; TSC mean = 3.99, SE = 2.16).
CONCLUSIONS: Entry into the canonical stage and other precursors of speech development were delayed in infants with TSC and may signal poor language and developmental outcomes. Future studies are planned to assess prediction of language and developmental outcomes using these measures in a larger sample and in more precisely comparable recording circumstances.

Keywords:  Autism spectrum disorder; Canonical babbling; Language; Tuberous sclerosis complex; Vocal development; Volubility

DOI:  https://doi.org/10.1016/j.pediatrneurol.2021.08.009
Eur J Immunol. 2021 Oct 14.

mTOR-dependent immunometabolism as Achilles' heel of anticancer therapy.

Clarissa Braun, Thomas Weichhart.

  Immune cells are important constituents of the tumor microenvironment and essential in eradicating tumor cells during conventional therapies or novel immunotherapies. The mechanistic target of rapamycin (mTOR) signaling pathway senses the intra- and extracellular nutrient status, growth factor supply and cell stress-related changes to coordinate cellular metabolism and activation dictating effector and memory functions in mainly all hematopoietic immune cells. In addition, the mTOR complex 1 (mTORC1) and mTORC2 are frequently deregulated and become activated in cancer cells to drive cell transformation, survival, neovascularization, and invasion. In this review we provide an overview of the influence of mTOR complexes on immune and cancer cell function and metabolism. We discuss how mTOR inhibitors aiming to target cancer cells will influence immunometabolic cell functions participating either in anti-tumor responses or favoring tumor cell progression in individual immune cells. We suggest immunometabolism as the weak spot of anticancer therapy and propose to evaluate patients according to their predominant immune cell subtype in the cancer tissue. Advances in metabolic drug development that hold promise for more effective treatments in different types of cancer will have to consider their effects on the immune system. This article is protected by copyright. All rights reserved.

Keywords:  Immunometabolism; cancer treatment; immunotherapy; mTORC1; tumor microenvironment

DOI:  https://doi.org/10.1002/eji.202149270
J Biol Chem. 2021 Oct 08. pii: S0021-9258(21)01096-6. [Epub ahead of print] 101291

Tyrosine Phosphorylation of DEPTOR Functions as a Molecular Switch to Activate mTOR Signaling.

Laurence M Gagné, Nadine Morin, Noémie Lavoie, Nicolas Bisson, Jean-Philippe Lambert, Frédérick A Mallette, Marc-Étienne Huot.

  Metabolic dysfunction is a major driver of tumorigenesis. The serine/threonine kinase mTOR constitutes a key central regulator of metabolic pathways promoting cancer cell proliferation and survival. mTOR activity is regulated by metabolic sensors as well as by numerous factors comprising the PTEN/PI3K/AKT canonical pathway, which are often mutated in cancer. However, some cancers displaying constitutively active mTOR do not carry alterations within this canonical pathway, suggesting alternative modes of mTOR regulation. Since DEPTOR, an endogenous inhibitor of mTOR, was previously found to modulate both mTOR complexe 1 and 2, we investigated the different post-transltionnal modification that could affect its inhibitory function. We found that tyrosine 289 phosphorylation of DEPTOR impairs its interaction with mTOR, leading to increased mTOR activation. Using proximity biotinylation assays, we identified SYK (Spleen tyrosine kinase) as a kinase involved in DEPTOR tyrosine 289 phosphorylation in an ephrin (EPH) receptor-dependent manner. Altogether, our work reveals that phosphorylation of tyrosine 289 of DEPTOR represents a novel molecular switch involved in the regulation of both mTORC1 and mTORC2.

Keywords:  DEPTOR; EPHB2; mTOR; tyrosine phosphorylation

DOI:  https://doi.org/10.1016/j.jbc.2021.101291
Curr Neuropharmacol. 2021 Oct 05.

Perspective on mTOR-dependent Protection in Status Epilepticus.

Francesca Biagioni, Roberta Celli, Filippo Sean Giorgi, Ferdinando Nicoletti, Francesco Fornai.

   BACKGROUND: The piriform cortex known as area tempestas owns a high propensity to trigger limbic epileptic seizures. Recent studies on human patients indicate that a resection containing the piriform cortex produces a marked improvement in patients suffering from intractable limbic seizures. This calls for looking back pharmacological and anatomical data on area tempestas. Within the piriform cortex status epilepticus can be induced by impairing desensitization of AMPA receptors. The mechanistic target of rapamycin complex1 (mTORC1) is a promising candidate. <P> Objective: The present perspective joins the novel role of the piriform cortex with recent evidence on the modulation of AMPA receptors under the influence of mTORC1. This is based on recent evidence and preliminary data, which lead to formulate an interaction between mTORC1 and AMPA receptors to mitigate the onset of long-lasting, self-sustaining, neurotoxic status epilepticus. <P> Methods: The perspective grounds its method on recent literature along with the actual experimental procedure to elicit status epilepticus from the piriform cortex and the method to administer the mTORC1 inhibitor rapamycin to mitigate seizure expression and brain damage. <P> Results: The available and present perspective converge to show that rapamycin may disrupt the seizure circuitry initiated in the piriform cortex to mitigate seizure duration, severity, and brain damage. <P> Conclusions: The perspective offered by this manuscript provides a novel scenario to understand refractory epilepsy and self-sustaining status epilepticus. This is expected to provide a beneficial outcome in patients suffering from temporal lobe epilepsy.

Keywords:  area tempestas; autophagy; mTOR; piriform cortex; rapamycin; status epilepticus

DOI:  https://doi.org/10.2174/1570159X19666211005152618
Ann Pathol. 2021 Oct 07. pii: S0242-6498(21)00166-8. [Epub ahead of print]

[Renal carcinoma with leiomyomatous stroma and osseous metaplasia from a patient diagnosed with a tuberous sclerosis complex].

Camille Gandon, Marjorie Gournay, Frédéric Dugay, Karim Bensalah, Romain Mathieu, Grégory Verhoest, Benoît Peyronnet, Marc-Antoine Belaud-Rotureau, Nathalie Rioux-Leclercq, Solène-Florence Kammerer-Jacquet.

  Renal cell carcinoma with leiomyomatous stroma is a rare and poorly described histopathological entity. Here we report a unique case with osseous metaplasia, in a 31-year-old man recently diagnosed with a tuberous sclerosis complex (TSC2 gene mutation). Partial nephrectomy was performed. Histologically, the epithelial component was made up of papillary and alveolar structures with clear to eosinophilic cytoplasm, and basally located nuclei. The cells are surrounded by an abundant smooth muscle stroma with focally osseous metaplasia. The tumor was positive for carbonic anhydrase IX, cytokeratin 7, cytokeratin 20, and CD10, and negative for TFE3. This emerging entity is highly correlated to tuberous sclerosis complex, which justifies a screening for the syndrome when this diagnosis is made.

Keywords:  Carcinome à cellules rénales; Leiomyomatous stroma; Mutation TSC2; Métaplasie osseuse; Osseous metaplasia; Renal cell carcinoma; Sclérose tubéreuse; Stroma léiomyomateux; TSC2 gene mutation; Tuberous sclerosis

DOI:  https://doi.org/10.1016/j.annpat.2021.06.005
Clin Case Rep. 2021 Oct;9(10): e04933

Incidental case finding of a 19-year-old woman with Tuberous Sclerosis Complex: A step-wise Multidisciplinary approach.

Sajjad Ali, Samahir Tariq Khan, Hamza Usman, Ali Hamza Khan, Zain Douba, Murtaza Ali.

  Radiological imaging plays a vital role in clinically diagnosing TSC. TSC prognosis is largely determined by the severity and the extent of the systems affected by it. TSC patients are symptomatically managed, since no cure is present. Healthcare professionals must frequently check-up TSC patients who have a lifelong disorder.

Keywords:  MRI; neurocutaneous; shagreen patch; tuberous sclerosis complex

DOI:  https://doi.org/10.1002/ccr3.4933
Behav Brain Res. 2021 Oct 09. pii: S0166-4328(21)00513-1. [Epub ahead of print]417 113625

GluN2A-ERK-mTOR pathway confers a vulnerability to LPS-induced depressive-like behaviour.

Ester Francija, Iva Lukic, Zorica Petrovic, Zeljka Brkic, Milos Mitic, Jelena Radulovic, Miroslav Adzic.

  Inflammation plays a key role in the pathogenesis of the major depressive disorder. Namely, neuroinflammation can induce the production of neuroactive metabolites that interfere with N-methyl-D-aspartate receptors (NMDAR)-mediated glutamatergic neurotransmission and contribute to depressive-like behaviour. On the other hand, mammalian target of rapamycin (mTOR) activity with synaptogenic effects is the main mediator of antidepressant effects of several potent NMDAR antagonists. In this study, we investigated the specific role of GluN2A subunits of NMDAR on the activity of mTOR signaling and behaviour in lipopolysaccharide (LPS)-induces model of depression. The results showed that mice lacking GluN2A subunit did not display depressive-like behavior after the immune challenge, opposite to LPS-treated wild-type mice. Specifically, in GluN2A knockout mice, we estimated the activity of the mTOR pathway in the hippocampus and prefrontal cortex (PFC) by measuring synaptic levels of upstream regulators (p-Akt, p-ERK, and p-GSK3β) and downstream effectors (p-mTOR, and p-p70S6K) of mTOR activity. In addition, we assessed the changes in the levels of two important synaptic markers, GluA1 and PSD-95. Contrary to downregulated mTOR signaling and decreased synaptic markers in LPS-treated wild-type animals, the resilience of GluN2A KO mice to depressive-like behaviour was paralleled with sustained mTOR signaling activity synaptic stability in hippocampus and PFC. Finally, we disclosed that resistance of GluN2A knockouts to LPS-induced depressive-like behavior was ERK-dependent. These findings demonstrate that GluN2A-ERK-mTOR signaling is a vulnerability factor of inflammation-related depressive behaviour, making this signaling pathway the promising target for developing novel antidepressants.

Keywords:  GluN2A knockout mice; Glutamatergic neurotransmission; LPS-induced depression; Synaptosomes; mTOR signaling

DOI:  https://doi.org/10.1016/j.bbr.2021.113625
Gene. 2021 Oct 11. pii: S0378-1119(21)00587-4. [Epub ahead of print] 145992

Everolimus accelerates Erastin and RSL3-induced ferroptosis in renal cell carcinoma.

Wang Yangyun, Shi Guowei, Shi Shufen, Yao Jie, Yu Rui, Ren Yu.

  Renal cell carcinoma (RCC) is a common type of urological cancer and is often diagnosed at an advanced stage. Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), is used as second-line therapy for sorafenib- or sunitinib-refractory metastatic RCC. However, the clinical benefits of Everolimus are often hampered by drug resistance. Ferroptosis is a novel form of regulated cell death that has recently been implicated in the development and therapeutic responses to different cancers. RSL3 ((1S,3R)-RSL3) and Erastin are two experimental compounds that can induce ferroptosis. In the present study, we evaluated the anti-tumor effects of Everolimus in combination with RSL3 or Erastin in RCC. Everolimus and RSL3/Erastin could synergistically inhibit the viability and induce ferroptosis in RCC cells. Mechanistically, the inhibition of the mTOR-4EBP1 axis was found to be essential for the synergistic effects of Everolimus and RSL3/Erastin. Moreover, the forced expression of GPX4 abrogated ferroptosis induced by the combined treatment of Everolimus and RSL3/Erastin. Taken together, these results demonstrated that Everolimus in combination with RSL3/Erastin is a promising therapeutic option for RCC treatment and it may also help to overcome the limitation in clinical applicability of Everolimus.

Keywords:  Erastin; Everolimus; RSL3; Renal cell carcinoma; ferroptosis; mTOR

DOI:  https://doi.org/10.1016/j.gene.2021.145992