bims-tubesc 2021-04-18 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2021–04–18
twelve papers selected by

mTOR inhibitor improves autistic-like behaviors related to Tsc2 haploinsufficiency but not following developmental status epilepticus.
A Web of Science-based scientometric analysis about mammalian target of rapamycin signaling pathway in kidney disease from 1986 to 2020.
Activated p53 in the anti-apoptotic milieu of tuberous sclerosis gene mutation induced diseases leads to cell death if thioredoxin reductase is inhibited.
Are HFOs in the Intra-operative ECoG Related to Hippocampal Sclerosis, Volume and IQ?
Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish.
How can we turn the PI3K/AKT/mTOR pathway down? Insights into inhibition and treatment of cancer.
The dynamic mechanism of 4E-BP1 recognition and phosphorylation by mTORC1.
mTOR activation initiates renal cell carcinoma development by coordinating ERK and p38MAPK.
Beyond Baby Siblings-Expanding the Definition of "High-Risk Infants" in Autism Research.
VEGFR Inhibitors for Uterine Metastatic Perivascular Epithelioid Tumors (PEComa) Resistant to mTOR Inhibitors. A Case Report and Review of Literature.
mTORC2 controls the activity of PKC and Akt by phosphorylating a conserved TOR interaction motif.
Primary cardiac tumours: how well can prenatal diagnosis "predict" postnatal outcome?

J Neurodev Disord. 2021 Apr 17. 13(1): 14

mTOR inhibitor improves autistic-like behaviors related to Tsc2 haploinsufficiency but not following developmental status epilepticus.

Tomas Petrasek, Iveta Vojtechova, Ondrej Klovrza, Klara Tuckova, Cestmir Vejmola, Jakub Rak, Anna Sulakova, Daniel Kaping, Nadine Bernhardt, Petrus J de Vries, Jakub Otahal, Robert Waltereit.

   BACKGROUND: Tuberous sclerosis complex (TSC), a multi-system genetic disorder often associated with autism spectrum disorder (ASD), is caused by mutations of TSC1 or TSC2, which lead to constitutive overactivation of mammalian target of rapamycin (mTOR). In several Tsc1+/- and Tsc2+/- animal models, cognitive and social behavior deficits were reversed by mTOR inhibitors. However, phase II studies have not shown amelioration of ASD and cognitive deficits in individuals with TSC during mTOR inhibitor therapy. We asked here if developmental epilepsy, common in the majority of individuals with TSC but absent in most animal models, could explain the discrepancy.
METHODS: At postnatal day P12, developmental status epilepticus (DSE) was induced in male Tsc2+/- (Eker) and wild-type rats, establishing four experimental groups including controls. In adult animals (n = 36), the behavior was assessed in the paradigms of social interaction test, elevated plus-maze, light-dark test, Y-maze, and novel object recognition. The testing was carried out before medication (T1), during a 2-week treatment with the mTOR inhibitor everolimus (T2) and after an 8-week washing-out (T3). Electroencephalographic (EEG) activity was recorded in a separate set of animals (n = 18).
RESULTS: Both Tsc2+/- mutation and DSE caused social behavior deficits and epileptiform EEG abnormalities (T1). Everolimus led to a persistent improvement of the social deficit induced by Tsc2+/-, while deficits related to DSE did not respond to everolimus (T2, T3).
CONCLUSIONS: These findings may contribute to an explanation why ASD symptoms in individuals with TSC, where comorbid early-onset epilepsy is common, were not reliably ameliorated by mTOR inhibitors in clinical studies.

Keywords:  Autism spectrum disorders; Developmental status epilepticus; Everolimus; TSC; Tuberous sclerosis complex; mTOR

DOI:  https://doi.org/10.1186/s11689-021-09357-2
Transl Androl Urol. 2021 Mar;10(3): 1006-1017

A Web of Science-based scientometric analysis about mammalian target of rapamycin signaling pathway in kidney disease from 1986 to 2020.

Lian-Zhong Wu, Yi-Qin Weng, Yi-Xin Ling, Shu-Juan Zhou, Xiao-Kai Ding, Si-Qi Wu, Kang Yu, Song-Fu Jiang, Yi Chen.

   Background: The mammalian target of rapamycin (mTOR) signaling pathway is vital for the regulation of cell metabolism, growth and proliferation in the kidney. This study aims to show current research focuses and predict future trends about mTOR pathway in kidney disease by the methods of scientometric analysis.
Methods: We referred to publications from the Web of ScienceTM Core Collection (WoSCC) Database. Carrot2, VOSviewer and CiteSpace programs were applied to evaluate the distribution and contribution of authors, institutes and countries/regions of extensive bibliographic metadata, show current research focuses and predict future trends in kidney disease's area.
Results: Until July 10, 2020, there are 2,585 manuscripts about mTOR signaling pathway in kidney disease in total and every manuscript is cited 27.39 times on average. The big name of course is the United States. Research hot spots include "diabetic nephropathy", "kidney transplantation", "autosomal dominant polycystic kidney disease", "tuberous sclerosis complex", "renal cell carcinoma" and "autophagy". Seven key clusters are detected, including "kidney transplantation", "autosomal dominant polycystic kidney disease", "renal transplantation", "renal cell carcinoma", "hamartin", "autophagy" and "tuberous sclerosis complex".
Conclusions: Diabetic nephropathy, kidney transplantation, autosomal dominant polycystic kidney disease, tuberous sclerosis complex, renal cell carcinoma and autophagy are future research hot spots by utilizing scientometric analysis. In the future, it is necessary to research these fields.

Keywords:  Bibliometrics; CiteSpace; TOR serine-threonine kinases; VOSviewer; kidney diseases

DOI:  https://doi.org/10.21037/tau-20-1469
Apoptosis. 2021 Apr 16.

Activated p53 in the anti-apoptotic milieu of tuberous sclerosis gene mutation induced diseases leads to cell death if thioredoxin reductase is inhibited.

ElHusseiny M M Abdelwahab, Judit Bovari-Biri, Gabor Smuk, Janos Fillinger, Donald McPhail, Vera P Krymskaya, Judit E Pongracz.

  Tuberous sclerosis, angiomyolipoma and lymphangioleiomyomatosis are a group of diseases characterized by mutation in tuberous sclerosis genes (TSC 1-2). TSC mutation leads to continuous activation of the mTOR pathway that requires adaptation to increased ATP requirement. With limited treatment options, there is an increasing demand to identify novel therapeutic targets and to understand the correlations between mTOR pathway activation and the lack of cell death in the presence of TSC mutation. In the current study, we demonstrate deregulation of p53 controlled and mitochondria associated cell death processes. The study also reveals that treatment of TSC mutant cells with the drug candidate Proxison combined with reduced concentration of rapamycin can increase production of reactive oxygen species (ROS), can modify miRNA expression pattern associated with p53 regulation and can reduce cell viability.

Keywords:  Apoptosis; MTOR; P53; ROS; TSC

DOI:  https://doi.org/10.1007/s10495-021-01670-4
Front Neurol. 2021 ;12 645925

Are HFOs in the Intra-operative ECoG Related to Hippocampal Sclerosis, Volume and IQ?

RESPect Database Study Group

  Temporal lobe epilepsy (TLE) is the most common form of refractory focal epilepsy and is often associated with hippocampal sclerosis (HS) and cognitive disturbances. Over the last decade, high frequency oscillations (HFOs) in the intraoperative electrocorticography (ioECoG) have been proposed to be biomarkers for the delineation of epileptic tissue but hippocampal ripples have also been associated with memory consolidation. Healthy hippocampi can show prolonged ripple activity in stereo- EEG. We aimed to identify how the HFO rates [ripples (80-250 Hz, fast ripples (250-500 Hz); prolonged ripples (80-250 Hz, 200-500 ms)] in the pre-resection ioECoG over subtemporal area (hippocampus) and lateral temporal neocortex relate to presence of hippocampal sclerosis, the hippocampal volume quantified on MRI and the severity of cognitive impairment in TLE patients. Volumetric measurement of hippocampal subregions was performed in 47 patients with TLE, who underwent ioECoG. Ripples, prolonged ripples, and fast ripples were visually marked and rates of HFOs were calculated. The intellectual quotient (IQ) before resection was determined. There was a trend toward higher rates of ripples and fast ripples in subtemporal electrodes vs. the lateral neocortex (ripples: 2.1 vs. 1.3/min; fast ripples: 0.9 vs. 0.2/min). Patients with HS showed higher rates of subtemporal fast ripples than other patients (Z = -2.51, p = 0.012). Prolonged ripples were only found in the lateral temporal neocortex. The normalized ratio (smallest/largest) of hippocampal volume was correlated to pre-resection IQ (r = 0.45, p = 0.015). There was no correlation between HFO rates and hippocampal volumes or HFO rates and IQ. To conclude, intra-operative fast ripples were a marker for HS, but ripples and fast ripples were not linearly correlated with either the amount of hippocampal atrophy, nor for pre-surgical IQ.

Keywords:  cognition; epilepsy surgery; high frequency oscillations; hippocampal volumetry; mesial temporal lobe epilepsy

DOI:  https://doi.org/10.3389/fneur.2021.645925
Sci Rep. 2021 Apr 16. 11(1): 8392

Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish.

Masanori Inoue, Hiroaki Miyahara, Hiroshi Shiraishi, Nobuyuki Shimizu, Mika Tsumori, Kyoko Kiyota, Miwako Maeda, Ryohei Umeda, Tohru Ishitani, Reiko Hanada, Kenji Ihara, Toshikatsu Hanada.

Leucyl-tRNA synthetase (LARS) is an enzyme that catalyses the ligation of leucine with leucine tRNA. LARS is also essential to sensitize the intracellular leucine concentration to the mammalian target of rapamycin complex 1 (mTORC1) activation. Biallelic mutation in the LARS gene causes infantile liver failure syndrome type 1 (ILFS1), which is characterized by acute liver failure, anaemia, and neurological disorders, including microcephaly and seizures. However, the molecular mechanism underlying ILFS1 under LARS deficiency has been elusive. Here, we generated Lars deficient (larsb-/-) zebrafish that showed progressive liver failure and anaemia, resulting in early lethality within 12 days post fertilization. The atg5-morpholino knockdown and bafilomycin treatment partially improved the size of the liver and survival rate in larsb-/- zebrafish. These findings indicate the involvement of autophagy in the pathogenesis of larsb-/- zebrafish. Indeed, excessive autophagy activation was observed in larsb-/- zebrafish. Therefore, our data clarify a mechanistic link between LARS and autophagy in vivo. Furthermore, autophagy regulation by LARS could lead to development of new therapeutics for IFLS1.

DOI: https://doi.org/10.1038/s41598-021-87879-4
Expert Rev Anticancer Ther. 2021 Apr 15.

How can we turn the PI3K/AKT/mTOR pathway down? Insights into inhibition and treatment of cancer.

Said M Afify, Aung Ko Ko Oo, Ghmkin Hassan, Akimasa Seno, Masaharu Seno.

   INTRODUCTION: The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is a fundamental regulator of cell proliferation and survival. Dysregulation in this pathway leads to the development of cancer. Accumulating evidence indicates that dysregulation in this pathway is involved in cancer initiation, progression, and recurrence. However, the pathway consists of various signal transducing factors related with cellular events, such as transformation, tumorigenesis, cancer progression, and drug resistance. Therefore, it is very important to determine the targets in this pathway for cancer therapy. Although many drugs inhibiting this signaling pathway are in clinical trials or have been approved for treating solid tumors and hematologic malignancies, further understanding of the signaling mechanism is required to achieve better therapeutic efficacy.
AREAS COVERED: In this review, we have describe the PI3K/AKT/mTOR pathway in detail, along with its critical role in cancer stem cells, for identifying potential therapeutic targets. We also summarize the recent developments in different types of signaling inhibitors.
EXPERT OPINION: Downregulation of the PI3K/AKT/mTOR pathway is very important for treating all types of cancers. Thus, further studies are required to establish novel prognostic factors to support the current progress in cancer treatment with emphasis on this pathway.

Keywords:  4E-BP; AKT/PKB; HIF1-alpha; PI3K; RHEV; S6 kinase; Signaling pathway; TSC1/2; dual inhibitors; mTOR

DOI:  https://doi.org/10.1080/14737140.2021.1918001
Mol Cell. 2021 Apr 05. pii: S1097-2765(21)00226-4. [Epub ahead of print]

The dynamic mechanism of 4E-BP1 recognition and phosphorylation by mTORC1.

Raphael Böhm, Stefan Imseng, Roman P Jakob, Michael N Hall, Timm Maier, Sebastian Hiller.

  The activation of cap-dependent translation in eukaryotes requires multisite, hierarchical phosphorylation of 4E-BP by the 1 MDa kinase mammalian target of rapamycin complex 1 (mTORC1). To resolve the mechanism of this hierarchical phosphorylation at the atomic level, we monitored by NMR spectroscopy the interaction of intrinsically disordered 4E binding protein isoform 1 (4E-BP1) with the mTORC1 subunit regulatory-associated protein of mTOR (Raptor). The N-terminal RAIP motif and the C-terminal TOR signaling (TOS) motif of 4E-BP1 bind separate sites in Raptor, resulting in avidity-based tethering of 4E-BP1. This tethering orients the flexible central region of 4E-BP1 toward the mTORC1 kinase site for phosphorylation. The structural constraints imposed by the two tethering interactions, combined with phosphorylation-induced conformational switching of 4E-BP1, explain the hierarchy of 4E-BP1 phosphorylation by mTORC1. Furthermore, we demonstrate that mTORC1 recognizes both free and eIF4E-bound 4E-BP1, allowing rapid phosphorylation of the entire 4E-BP1 pool and efficient activation of translation. Finally, our findings provide a mechanistic explanation for the differential rapamycin sensitivity of the 4E-BP1 phosphorylation sites.

Keywords:  NMR spectroscopy; atypical kinase; hierarchical phosphorylation; intrinsically disordered protein; kinetic modelling; mTOR signaling; multi‑site binding; protein dynamics; target of rapamycin; translational control

DOI:  https://doi.org/10.1016/j.molcel.2021.03.031
Cancer Res. 2021 Apr 16. pii: canres.3979.2020. [Epub ahead of print]

mTOR activation initiates renal cell carcinoma development by coordinating ERK and p38MAPK.

Hongguang Wu, Dan He, Soma Biswas, Md Shafiquzzaman, Xin Zhou, Jean Charron, Yibin Wang, Bijaya K Nayak, Samy L Habib, Huijuan Liu, Baojie Li.

Renal cell carcinoma (RCC) mainly originates from renal proximal tubules. Intriguingly, disruption of genes frequently mutated in human RCC samples thus far has only generated RCC originated from other renal tubule parts in mouse models. This hampers our understanding of the pathogenesis of RCC. Here we show that mTOR signaling, often activated in RCC samples, initiates RCC development from renal proximal tubules. Ablation of Tsc1, encoding an mTOR suppressor, in proximal tubule cells led to multiple precancerous renal cysts. mTOR activation increased MEK1 expression and ERK activation, and Mek1 ablation or inhibition diminished cyst formation in Tsc1-deficient mice. mTOR activation also increased MKK6 expression and p38MAPK activation, and ablation of the p38α-encoding gene further enhanced cyst formation and led to RCC with clear cell RCC features. Mechanistically, Tsc1 deletion induced p53 and p16 expression in a p38MAPK-dependent manner, and deleting Tsc1 and Trp53 or Cdkn2a (encoding p16) enhanced renal cell carcinogenesis. Thus, mTOR activation in combination with inactivation of the p38MAPK-p53/p16 pathway drives RCC development from renal proximal tubules. Moreover, this study uncovers previously unidentified mechanisms by which mTOR controls cell proliferation and suggests the MEK-ERK axis to be a potential target for treatment of RCC.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-3979
Curr Psychiatry Rep. 2021 Apr 16. 23(6): 34

Beyond Baby Siblings-Expanding the Definition of "High-Risk Infants" in Autism Research.

Nicole M McDonald, Shafali S Jeste.

   PURPOSE OF REVIEW: Much of our understanding of early development in children with autism spectrum disorder (ASD) comes from studies of children with a family history of autism. We reviewed the current literature on neurodevelopmental profiles and autism prevalence from other high-risk infant groups to expose gaps and inform next steps. We focused on infants with early medical risk (e.g., preterm birth) and genetic risk (tuberous sclerosis complex [TSC]).
RECENT FINDINGS: About 7% of very preterm infants are later diagnosed with ASD. Prospective studies of early development outside of familial-risk infants are rare; however, recent work within preterm and TSC infants suggests interesting similarities and differences from infants with a family history of ASD. It is essential that we extend our knowledge of early markers of ASD beyond familial-risk infants to expand our knowledge of autism as it emerges in order to develop better, more individualized early interventions.

Keywords:  Autism spectrum disorder; High-risk infants

DOI:  https://doi.org/10.1007/s11920-021-01243-x
Front Oncol. 2021 ;11 641376

VEGFR Inhibitors for Uterine Metastatic Perivascular Epithelioid Tumors (PEComa) Resistant to mTOR Inhibitors. A Case Report and Review of Literature.

Aikaterini Liapi, Patrice Mathevet, Fernanda G Herrera, Delfyne Hastir, Apostolos Sarivalasis.

  Uterine perivascular epithelioid cell tumors (PEComas) are rare neoplasms. PI3K/AKT/mTOR pathway upregulation is critical for their pathogenesis and is often associated with TSC1/TSC2 inactivation. Although first line mTOR inhibitors are an effective treatment, metastatic PEComas eventually progress. A 53-year-old woman presented a 4-month history of post-menopausal vaginal bleeding. Clinical and radiological examination detected a uterine mass and a single S1 bone lesion. The patient underwent a radical hysterectomy and bone biopsy. The anatomopathological evaluation concluded to an oligo-metastatic uterine PEComa. The tumor harbored a heterozygous deletion of 9q34 that contains the TSC1 gene. Concerning the primary lesion, the resection was complete and the single bone metastasis was treated with radiotherapy. Three months later, the patient presented bone, lung and subcutaneous metastatic progression. An everolimus and denosumab treatment was initiated. After 2 years of treatment, a clinically significant bone, lung and subcutaneous progression was detected. Following a literature review of the possible therapeutic options, we initiated a second line treatment by pazopanib. This treatment resulted in regression of the subcutaneous lesions and stability of lung and bone metastases. In this challenging, rare setting, our report suggests single agent, anti-angiogenic, tyrosine kinase inhibitor to be effective as second line treatment of metastatic uterine PEComa progressing on mTOR inhibitors.

Keywords:  PEComa; VEGFR; mTOR; second line; soft tissue sarcomas; uterine perivascular epithelioid cell tumor

DOI:  https://doi.org/10.3389/fonc.2021.641376
Sci Signal. 2021 Apr 13. pii: eabe4509. [Epub ahead of print]14(678):

mTORC2 controls the activity of PKC and Akt by phosphorylating a conserved TOR interaction motif.

Timothy R Baffi, Gema Lordén, Jacob M Wozniak, Andreas Feichtner, Wayland Yeung, Alexandr P Kornev, Charles C King, Jason C Del Rio, Ameya J Limaye, Julius Bogomolovas, Christine M Gould, Ju Chen, Eileen J Kennedy, Natarajan Kannan, David J Gonzalez, Eduard Stefan, Susan S Taylor, Alexandra C Newton.

The complex mTORC2 is accepted to be the kinase that controls the phosphorylation of the hydrophobic motif, a key regulatory switch for AGC kinases, although whether mTOR directly phosphorylates this motif remains controversial. Here, we identified an mTOR-mediated phosphorylation site that we termed the TOR interaction motif (TIM; F-x3-F-pT), which controls the phosphorylation of the hydrophobic motif of PKC and Akt and the activity of these kinases. The TIM is invariant in mTORC2-dependent AGC kinases, is evolutionarily conserved, and coevolved with mTORC2 components. Mutation of this motif in Akt1 and PKCβII abolished cellular kinase activity by impairing activation loop and hydrophobic motif phosphorylation. mTORC2 directly phosphorylated the PKC TIM in vitro, and this phosphorylation event was detected in mouse brain. Overexpression of PDK1 in mTORC2-deficient cells rescued hydrophobic motif phosphorylation of PKC and Akt by a mechanism dependent on their intrinsic catalytic activity, revealing that mTORC2 facilitates the PDK1 phosphorylation step, which, in turn, enables autophosphorylation. Structural analysis revealed that PKC homodimerization is driven by a TIM-containing helix, and biophysical proximity assays showed that newly synthesized, unphosphorylated PKC dimerizes in cells. Furthermore, disruption of the dimer interface by stapled peptides promoted hydrophobic motif phosphorylation. Our data support a model in which mTORC2 relieves nascent PKC dimerization through TIM phosphorylation, recruiting PDK1 to phosphorylate the activation loop and triggering intramolecular hydrophobic motif autophosphorylation. Identification of TIM phosphorylation and its role in the regulation of PKC provides the basis for AGC kinase regulation by mTORC2.

DOI: https://doi.org/10.1126/scisignal.abe4509
Bratisl Lek Listy. 2021 ;122(5): 315-319

Primary cardiac tumours: how well can prenatal diagnosis "predict" postnatal outcome?

H Habanova, M Kaldararova, P Tittel, L Kovacikova, A Cunderlik, I Rusnak.

OBJECTIVE: Primary foetal cardiac tumours are rare congenital malformations. They can cause a flow obstruction, arrhythmias and can lead to cardiac failure, hydrops or death. Postnatal management is based on patient´s clinical and hemodynamic impairment.
METHODS: We retrospectively reviewed data from 2009-2019 from our gynaecology clinic and also data regarding postnatal follow-up from our partner paediatric institution.
RESULTS: In this period, we diagnosed six cases with foetal cardiac tumours. In four cases, multiple rhabdomyomas were present. Three patients did not have serious complications pre- or postnatally. In one case, tumours were obliterating both the inflow and the outflow of the left ventricle. The child died at three months of age. Tuberous sclerosis was confirmed in all the cases with rhabdomyomas. One child had a fibroma filling the left ventricle. Despite an uneventful prenatal period, the patient got postnatally symptomatic. Tumour was considered inoperable and the child died at the age of five months. In one case a single right ventricular unspecified tumour was diagnosed, without any complications.
CONCLUSION: Prognosis closely depends on early diagnosis, clinical manifestations and the possibility of surgical tumour removal if necessary. In confirmed rhabdomyomas, tests for tuberous sclerosis are mandatory (Tab. 1, Fig. 2, Ref. 18). Text in PDF www.elis.sk Keywords: rhabdomyoma, fibroma, prenatal diagnosis, ultrasound, tuberous sclerosis.

DOI: https://doi.org/10.4149/BLL_2021_053