bims-tubesc 2021-05-02 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2021–05–02
fiveteen papers selected by

Current Approaches and Future Directions for the Treatment of mTORopathies.
Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies.
The Characterization of a Subependymal Giant Astrocytoma-Like Cell Line from Murine Astrocyte with mTORC1 Hyperactivation.
The characteristics and optimal treatment of urolithiasis associated with tuberous sclerosis complex.
TSC1 and TSC2 Genotype in Tuberous Sclerosis Complex: Are Other Manifestations of this Multisystem Disease Affected by Genotype?
Frequency, Progression, and Current Management: Report of 16 New Cases of Nonfunctional Pancreatic Neuroendocrine Tumors in Tuberous Sclerosis Complex and Comparison With Previous Reports.
Sirolimus-based immunosuppression improves the prognosis of liver Transplantation Recipients with low TSC1/2 expression in hepatocellular carcinoma beyond the Milan Criteria.
Connectivity Map Analysis of a Single-Cell RNA-Sequencing -Derived Transcriptional Signature of mTOR Signaling.
Cardiac Rhabdomyoma: A Surrogate Diagnosis of Tuberous Sclerosis Complex in a Newborn Baby: Case Report from Tikur Anbessa University Hospital.
4E-BP2-dependent translation in cerebellar Purkinje cells controls spatial memory but not autism-like behaviors.
Maintenance Therapy With Everolimus for Subependymal Giant Cell Astrocytoma in Patients With Tuberous Sclerosis - Final Results From the EMINENTS Study.
Use of Topical Rapamycin as Maintenance Treatment after a Single Session of Fractionated CO2 Laser Ablation: A Method to Enhance Percutaneous Drug Delivery.
Protein Acetylation at the Interface of Genetics, Epigenetics and Environment in Cancer.
Leucine-sensing mechanism of leucyl-tRNA synthetase 1 for mTORC1 activation.
Rapamycin, but not minocycline, significantly alters ultrasonic vocalization behavior in C57Bl/6J pups in a flurothyl seizure model.

Dev Neurosci. 2021 Apr 28. 1-16

Current Approaches and Future Directions for the Treatment of mTORopathies.

Vasiliki Karalis, Helen S Bateup.

  The mechanistic target of rapamycin (mTOR) is a kinase at the center of an evolutionarily conserved signaling pathway that orchestrates cell growth and metabolism. mTOR responds to an array of intra- and extracellular stimuli and in turn controls multiple cellular anabolic and catabolic processes. Aberrant mTOR activity is associated with numerous diseases, with particularly profound impact on the nervous system. mTOR is found in two protein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which are governed by different upstream regulators and have distinct cellular actions. Mutations in genes encoding for mTOR regulators result in a collection of neurodevelopmental disorders known as mTORopathies. While these disorders can affect multiple organs, neuropsychiatric conditions such as epilepsy, intellectual disability, and autism spectrum disorder have a major impact on quality of life. The neuropsychiatric aspects of mTORopathies have been particularly challenging to treat in a clinical setting. Current therapeutic approaches center on rapamycin and its analogs, drugs that are administered systemically to inhibit mTOR activity. While these drugs show some clinical efficacy, adverse side effects, incomplete suppression of mTOR targets, and lack of specificity for mTORC1 or mTORC2 may limit their utility. An increased understanding of the neurobiology of mTOR and the underlying molecular, cellular, and circuit mechanisms of mTOR-related disorders will facilitate the development of improved therapeutics. Animal models of mTORopathies have helped unravel the consequences of mTOR pathway mutations in specific brain cell types and developmental stages, revealing an array of disease-related phenotypes. In this review, we discuss current progress and potential future directions for the therapeutic treatment of mTORopathies with a focus on findings from genetic mouse models.

Keywords:  Epilepsy; Neurodevelopmental disorders; PTEN; Rapamycin; Raptor; Rictor; Tuberous sclerosis complex; mTORC1; mTORC2; mTORopathy

DOI:  https://doi.org/10.1159/000515672
Front Neuroanat. 2021 ;15 664695

Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies.

Lena H Nguyen, Angélique Bordey.

  Hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) due to mutations in genes along the PI3K-mTOR pathway and the GATOR1 complex causes a spectrum of neurodevelopmental disorders (termed mTORopathies) associated with malformation of cortical development and intractable epilepsy. Despite these gene variants' converging impact on mTORC1 activity, emerging findings suggest that these variants contribute to epilepsy through both mTORC1-dependent and -independent mechanisms. Here, we review the literature on in utero electroporation-based animal models of mTORopathies, which recapitulate the brain mosaic pattern of mTORC1 hyperactivity, and compare the effects of distinct PI3K-mTOR pathway and GATOR1 complex gene variants on cortical development and epilepsy. We report the outcomes on cortical pyramidal neuronal placement, morphology, and electrophysiological phenotypes, and discuss some of the converging and diverging mechanisms responsible for these alterations and their contribution to epileptogenesis. We also discuss potential therapeutic strategies for epilepsy, beyond mTORC1 inhibition with rapamycin or everolimus, that could offer personalized medicine based on the gene variant.

Keywords:  GATOR1 complex; cortical development; epilepsy; focal cortical dysplasia; in utero electroporation; mTOR; neuron migration; tuberous sclerosis complex

DOI:  https://doi.org/10.3389/fnana.2021.664695
Int J Mol Sci. 2021 Apr 16. pii: 4116. [Epub ahead of print]22(8):

The Characterization of a Subependymal Giant Astrocytoma-Like Cell Line from Murine Astrocyte with mTORC1 Hyperactivation.

Xin Tang, Gabrielle Angst, Michael Haas, Fuchun Yang, Chenran Wang.

  Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in TSC1 (hamartin) or TSC2 (tuberin), crucial negative regulators of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. TSC affects multiple organs including the brain. The neurologic manifestation is characterized by cortical tubers, subependymal nodules (SEN), and subependymal giant cell astrocytoma (SEGA) in brain. SEGAs may result in hydrocephalus in TSC patients and mTORC1 inhibitors are the current recommended therapy for SEGA. Nevertheless, a major limitation in the research for SEGA is the lack of cell lines or animal models for mechanistic investigations and development of novel therapy. In this study, we generated TSC1-deficient neural cells from spontaneously immortalized mouse astrocytes in an attempt to mimic human SEGA. The TSC1-deficient cells exhibit mTORC1 hyperactivation and characteristics of transition from astrocytes to neural stem/progenitor cell phenotypes. Rapamycin efficiently decreased mTORC1 activity of these TSC1-deficient cells in vitro. In vivo, TSC1-deficient cells could form SEGA-like tumors and Rapamycin treatment decreased tumor growth. Collectively, our study generates a novel SEGA-like cell line that is invaluable for studying mTORC1-driven molecular and pathological alterations in neurologic tissue. These SEGA-like cells also provide opportunities for the development of novel therapeutic strategy for TSC patients with SEGA.

Keywords:  SEGA-like tumorigenesis; TSC1; astrocyte; mTORC1; rapamycin

DOI:  https://doi.org/10.3390/ijms22084116
Int Urol Nephrol. 2021 Apr 25.

The characteristics and optimal treatment of urolithiasis associated with tuberous sclerosis complex.

Takashi Hatano, Katsuhisa Endo.

   PURPOSE: The most common renal symptoms of tuberous sclerosis complex (TSC) are angiomyolipomas (AMLs) and renal cysts; however, some patients with TSC also develop urolithiasis. We retrospectively investigated the characteristics and treatment of urolithiasis associated with TSC.
METHODS: We analyzed 142 patients who met the diagnostic criteria for TSC, of whom 20 (14.1%) had urolithiasis. We compared the patients' characteristics, urinary specific gravity, urine pH, serum calcium and intact parathyroid hormone in the urolithiasis and non-urolithiasis groups. In the urolithiasis group, the stone characteristics and various treatments were analyzed.
RESULTS: The antiepileptic drugs topiramate and zonisamide were more frequently administered to the urolithiasis group than the non-urolithiasis group (P = 0.013, P = 0.048, respectively). The urine specific gravity and urine pH levels were higher in the urolithiasis group than in the non-urolithiasis group (P = 0.005, P = 0.042, respectively). A multivariate logistic regression analysis demonstrated that urine-specific gravity (P = 0.018; odds ratio 1.471; 95% confidence interval 1.098-1.872) was a significant predictor of TSC-associated urolithiasis. Four patients could not receive extracorporeal shock wave lithotripsy due to the risk of bleeding from the AML.
CONCLUSION: Patients with TSC who have an increased urine specific gravity, alkaline urine, and a longer administration of topiramate and zonisamide tend to demonstrate an increased risk of developing urolithiasis and therefore such cases require adequate care. If urolithiasis is comorbid with TSC-associated AML, the treatment options are more limited in cases with multiple AMLs around the stone due to an increased risk of hemorrhage.

Keywords:  Renal angiomyolipoma; Topiramate; Tuberous sclerosis complex; Urine specific gravity; Urolithiasis; Zonisamide

DOI:  https://doi.org/10.1007/s11255-021-02871-1
Ann Am Thorac Soc. 2021 May;18(5): 775-777

TSC1 and TSC2 Genotype in Tuberous Sclerosis Complex: Are Other Manifestations of this Multisystem Disease Affected by Genotype?

Thomas N Darling, Elizabeth A Thiele, Joel Moss.

DOI: https://doi.org/10.1513/AnnalsATS.202012-1576ED
Front Neurol. 2021 ;12 627672

Frequency, Progression, and Current Management: Report of 16 New Cases of Nonfunctional Pancreatic Neuroendocrine Tumors in Tuberous Sclerosis Complex and Comparison With Previous Reports.

Kate Mowrey, Hope Northrup, Peyton Rougeau, S Shahrukh Hashmi, Darcy A Krueger, Daniel Ebrahimi-Fakhari, Alexander J Towbin, Andrew T Trout, Jamie K Capal, David Neal Franz, David Rodriguez-Buritica.

  Background: Tuberous sclerosis complex (TSC) is a genetic condition that causes benign tumors to grow in multiple organ systems. Nonfunctional pancreatic neuroendocrine tumors (PNETs) are a rare clinical feature of TSC with no specific guidelines outlined for clinical management at this time. Our purpose is to calculate the frequency of nonfunctional PNETs as well as characterize the presentation, current clinical management, and assess the impact of systemic mammalian target of rapamycin (mTOR) on nonfunctional PNETs in TSC. Methods: This retrospective chart review was performed by a query of the TS Alliance's Natural History Database and the Cincinnati Children's Hospital TSC Database for patients with nonfunctional PNET. Clinical data from these two groups was summarized for patients identified to have a nonfunctional PNET and compared to previously reported cases with TSC and nonfunctional PNETs. Results: Our calculated frequency of nonfunctional PNETs is 0.65%. We identified 16 individuals, nine males and seven females, with a median age of 18.0 years (interquartile range: -15.5 to 25.5). Just over half (56.3%, n = 9) of the patients provided results from genetic testing. Six had pathogenic variants in TSC2 whereas three had pathogenic variants in TSC1. The average age at PNET diagnosis was 15.0 years (range: 3-46 years). Almost all individuals were diagnosed with a PNET during routine TSC surveillance, 56.3% (n = 9) by MRI, 12.5% (n = 2) by CT, 25% (n = 4) by ultrasound, and 6.2% (n = 1) through a surgical procedure. Follow up after diagnosis involved 68.8% (n = 11) having serial imaging and nine of the sixteen individuals proceeding with surgical removal of the PNET. Eight individuals had a history of using systemic mTOR inhibitors. Tumor growth rate was slightly less in individuals taking an mTOR inhibitor (-0.8 mm/yr, IQR: -2.3 to 2.2) than those without (1.6 mm/yr; IQR: -0.99 to 5.01, p > 0.05). Conclusions: Nonfunctional PNETs occurred at younger ages in our TSC cohort and more commonly compared to ages and prevalence reported for the general population. PNETs in patients on systemic mTOR inhibitors had lower rates of growth. The outcome of this study provides preliminary evidence supporting the use of mTOR inhibitor therapy in conjunction with serial imaging as medical management for nonfunctional PNETs as an alternative option to invasive surgical removal.

Keywords:  abdominal imaging; nonfunctional; pancreatic neuroendocrine tumor; surveillance; tuberous sclerosis

DOI:  https://doi.org/10.3389/fneur.2021.627672
Eur J Surg Oncol. 2021 Apr 19. pii: S0748-7983(21)00407-8. [Epub ahead of print]

Sirolimus-based immunosuppression improves the prognosis of liver Transplantation Recipients with low TSC1/2 expression in hepatocellular carcinoma beyond the Milan Criteria.

Qianwei Ye, Sunbin Ling, Guangjiang Jiang, Qiaonan Shan, Shengjun Xu, Qifan Zhan, Yifeng Wu, Yuchen Liu, Shusen Zheng, Xiao Xu.

   BACKGROUND: The use of the immunosuppressive agent sirolimus (SRL) following liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) is controversial. Sirolimus is a typical mammalian target of rapamycin (mTOR) inhibitor, and tuberous sclerosis 1-tuberous sclerosis 2 complex (TSC1/TSC2) is an important negative effector in the mTOR pathway. In this study, we investigated the effect of SRL-based immunosuppression on the prognosis of LT recipients with HCC beyond the Milan criteria based on TSC1/2 expression and explored the effect of TSC1 on HCC in vitro and in vivo.
METHODS: We retrospectively analyzed 120 HCC patients who underwent LT in our hospital between January 1, 2015 and December 30, 2018. All patients had HCC beyond the Milan criteria and were divided into the SRL group (n = 50) and non-SRL group (n = 70). TSC1/2 expression levels in paraffin-embedded tissues were determined by immunohistochemistry (IHC) and then analyzed as subgroups. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method. TSC1 expression was silenced in Huh-7 and Bel-7402 cell lines for further cell function experiments.
RESULTS: 88.3% of patients were HBV LT recipients. The SRL group exhibited better DFS and OS compared to the non-SRL group (P = 0.02, P = 0.003). Subgroup (TSC1-based or TSC2-based) analyses revealed that patients with low TSC1 or TSC2 expression benefited from sirolimus (DFS: P = 0.046, OS: P = 0.006 for TSC1; DFS: P = 0.05, OS: P = 0.003 for TSC2) compared with patients with high expression. TSC1 knockdown in Huh-7 and Bel-7402 HCC cell lines activated the mTORC1 pathway and enhanced cell proliferation, migration and sensitivity to SRL in vitro and in vivo.
CONCLUSION: TSC1/2 expression could be used to predict the prognosis of patients with HCC beyond the Milan criteria who underwent SRL-based immunosuppression following LT. TSC1 knockdown promoted HCC malignancy and enhanced sensitivity to SRL.

Keywords:  Hepatocellular carcinoma; Liver transplantation; Prognosis; Sirolimus; TSC1/2

DOI:  https://doi.org/10.1016/j.ejso.2021.04.001
Int J Mol Sci. 2021 Apr 22. pii: 4371. [Epub ahead of print]22(9):

Connectivity Map Analysis of a Single-Cell RNA-Sequencing -Derived Transcriptional Signature of mTOR Signaling.

Naim Al Mahi, Erik Y Zhang, Susan Sherman, Jane J Yu, Mario Medvedovic.

  In the connectivity map (CMap) approach to drug repositioning and development, transcriptional signature of disease is constructed by differential gene expression analysis between the diseased tissue or cells and the control. The negative correlation between the transcriptional disease signature and the transcriptional signature of the drug, or a bioactive compound, is assumed to indicate its ability to "reverse" the disease process. A major limitation of traditional CMaP analysis is the use of signatures derived from bulk disease tissues. Since the key driver pathways are most likely dysregulated in only a subset of cells, the "averaged" transcriptional signatures resulting from bulk analysis lack the resolution to effectively identify effective therapeutic agents. The use of single-cell RNA-seq (scRNA-seq) transcriptomic assay facilitates construction of disease signatures that are specific to individual cell types, but methods for using scRNA-seq data in the context of CMaP analysis are lacking. Lymphangioleiomyomatosis (LAM) mutations in TSC1 or TSC2 genes result in the activation of the mTOR complex 1 (mTORC1). The mTORC1 inhibitor Sirolimus is the only FDA-approved drug to treat LAM. Novel therapies for LAM are urgently needed as the disease recurs with discontinuation of the treatment and some patients are insensitive to the drug. We developed methods for constructing disease transcriptional signatures and CMaP analysis using scRNA-seq profiling and applied them in the analysis of scRNA-seq data of lung tissue from naïve and sirolimus-treated LAM patients. New methods successfully implicated mTORC1 inhibitors, including Sirolimus, as capable of reverting the LAM transcriptional signatures. The CMaP analysis mimicking standard bulk-tissue approach failed to detect any connection between the LAM signature and mTORC1 signaling. This indicates that the precise signature derived from scRNA-seq data using our methods is the crucial difference between the success and the failure to identify effective therapeutic treatments in CMaP analysis.

Keywords:  LINCS; connectivity analysis; lymphangioleiomyomatosis; mTOR; single-cell

DOI:  https://doi.org/10.3390/ijms22094371
Ethiop J Health Sci. 2020 Jul 01. 30(4): 639-642

Cardiac Rhabdomyoma: A Surrogate Diagnosis of Tuberous Sclerosis Complex in a Newborn Baby: Case Report from Tikur Anbessa University Hospital.

Moges Tamirat, Beyene Ayalew.

   Background: Neonatal tuberous sclerosis complex is an autosomal dominant inherited disease characterized by high rate of neurological, cardiac and skin manifestations.
Case Presentation: We reported a 4 days old female neonate with respiratory distress, tachypnea, tachycardia and hypomelanotic macular lesions. Her chest X-ray and echocardiographic studies revealed cardiomegaly and multiple echogenic masses in the left and right ventricles, suggestive of cardiac rhabdomyoma. Furthermore, non-contrast brain magnetic resonance imaging revealed sub-ependymal nodules and cortical tubers. Therefore, a clinical diagnosis of neonatal tuberous sclerosis complex with heart failure was made. Then, the patient was initiated on diuretic treatment with oxygen by nasal catheter with subsequent improvement. Seizure was not occurred yet in the last three and half years of follow-up. Currently, the patient is thriving well with no symptoms.
Conclusion: Detection of prenatal or early neonatal age, cardiac rhabdomyoma is a useful clue to the diagnosis of tuberous sclerosis complex in neonates. Proper clinical evaluation of patients at the time of first contact prevents missing of findings such as skin macules and chest X-ray findings, which helped us to diagnose tuberous sclerosis complex in the present case.

Keywords:  Cardiac rhabdomyoma; Hypomelanotic macules; sub-ependymal nodules and cortical tubers; tuberous sclerosis complex

DOI:  https://doi.org/10.4314/ejhs.v30i4.19
Cell Rep. 2021 Apr 27. pii: S2211-1247(21)00352-1. [Epub ahead of print]35(4): 109036

4E-BP2-dependent translation in cerebellar Purkinje cells controls spatial memory but not autism-like behaviors.

Mehdi Hooshmandi, Vinh Tai Truong, Eviatar Fields, Riya Elizabeth Thomas, Calvin Wong, Vijendra Sharma, Ilse Gantois, Patricia Soriano Roque, Kleanthi Chalkiadaki, Neil Wu, Anindyo Chakraborty, Soroush Tahmasebi, Masha Prager-Khoutorsky, Nahum Sonenberg, Aparna Suvrathan, Alanna J Watt, Christos G Gkogkas, Arkady Khoutorsky.

  Recent studies have demonstrated that selective activation of mammalian target of rapamycin complex 1 (mTORC1) in the cerebellum by deletion of the mTORC1 upstream repressors TSC1 or phosphatase and tensin homolog (PTEN) in Purkinje cells (PCs) causes autism-like features and cognitive deficits. However, the molecular mechanisms by which overactivated mTORC1 in the cerebellum engenders these behaviors remain unknown. The eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2) is a central translational repressor downstream of mTORC1. Here, we show that mice with selective ablation of 4E-BP2 in PCs display a reduced number of PCs, increased regularity of PC action potential firing, and deficits in motor learning. Surprisingly, although spatial memory is impaired in these mice, they exhibit normal social interaction and show no deficits in repetitive behavior. Our data suggest that, downstream of mTORC1/4E-BP2, there are distinct cerebellar mechanisms independently controlling social behavior and memory formation.

Keywords:  4E-BP2; Purkinje cells; autism spectrum disorders; motor learning; spatial memory

DOI:  https://doi.org/10.1016/j.celrep.2021.109036
Front Neurol. 2021 ;12 581102

Maintenance Therapy With Everolimus for Subependymal Giant Cell Astrocytoma in Patients With Tuberous Sclerosis - Final Results From the EMINENTS Study.

Katarzyna Bobeff, Karolina Krajewska, Dobromila Baranska, Katarzyna Kotulska, Sergiusz Jozwiak, Wojciech Mlynarski, Joanna Trelinska.

  The aim of this EMINENTS prospective, single-center, open-label, single-arm study was to evaluate the cumulative efficacy and safety of reduced doses of everolimus (maintenance therapy) in patients with tuberous sclerosis and subependymal giant cell astrocytoma (SEGA). Methods: The trial included 15 patients who had undergone at least 12 months of treatment with a standard everolimus dose. The dose of everolimus was reduced to three times a week, with a daily dose as in standard regimen. Data of 14 patients were analyzed. SEGA volume (SV) was evaluated at study entry and subsequent time points by an experienced radiologist. Adverse events (AEs) noted during maintenance therapy were compared to the AEs of standard dose period. Results: Patients were followed over a mean duration 58.37 months (95%CI: 45.95-70.78). The differences in SEGA volume between subsequent time points (0, 3, 6,12, 18, 24, 36, 48, and 60 months) were not statistically significant (p = 0.16). At the end of the study, 7 out of 10 patients had stable SEGA volume. No clinical symptoms of progression were observed in any patients. No patient or tumor-related risk factors of progression were identified. Regarding AEs, infections (stomatitis, bronchitis, diarrhea) and laboratory abnormalities (neutropenia, anemia, hyperglycemia) occurred less frequently during maintenance therapy compared to the standard dose regimen. Conclusions: Final results from EMINENTS study confirm that maintenance therapy with everolimus might represent a rational therapeutic option for patients TSC and SEGA after effective full dose treatment. It could be an option for patients who experienced everolimus-related AEs, instead of discontinuation of therapy. Careful evaluation of possible progression, especially concerning first six months of maintenance therapy should be advised. Clinical Trial Registration: www.drks.de, identifier DRKS00005584.

Keywords:  MTOR inhibitor; everolimus; maintenance therapy; subependymal giant cell astrocytoma; tuberous sclerosis

DOI:  https://doi.org/10.3389/fneur.2021.581102
Ann Dermatol. 2019 Oct;31(5): 555-558

Use of Topical Rapamycin as Maintenance Treatment after a Single Session of Fractionated CO2 Laser Ablation: A Method to Enhance Percutaneous Drug Delivery.

Jongwook Oh, Jihee Kim, Won Jai Lee, Ju Hee Lee.

  Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder with an incidence of approximately 1 in 5,000 to 10,000 live births. TSC has various clinical manifestations such as multiple hamartomas in systemic organs, including the skin. Angiofibromas are the most common skin lesions in patients with TSC. Although benign, angiofibromas develop in childhood and puberty, and can be psychosocially disfiguring for patients. Skin lesions in TSC, specifically angiofibromas, have no significant risk of malignant transformation after puberty; thus, they require no treatment if not prominent. However, the presentation of TSC is important owing to its impact on patient cosmesis. Surgical treatment and laser therapy are the mainstream treatments for angiofibromas. Although the evidence is limited, topical mammalian target of rapamycin inhibitors such as sirolimus (rapamycin) are effective in facial angiofibroma treatment. We describe an adult patient with an angiofibroma who had an excellent response to treatment with topical rapamycin after a single session of carbon dioxide (CO2) laser ablation. The patient showed no sign of relapse or recurring lesions for a year. CO2 laser ablation may serve as a new paradigm of treatment for angiofibromas in TSC. Since the selection of laser devices can be limited for some institutions, we suggest a rather basic but highly effective approach for angiofibroma treatment that can be generally applied with the classic CO2 device.

Keywords:  Angiofibroma; CO2 laser; Sirolimus; Tuberous sclerosis complex

DOI:  https://doi.org/10.5021/ad.2019.31.5.555
Metabolites. 2021 Apr 01. pii: 216. [Epub ahead of print]11(4):

Protein Acetylation at the Interface of Genetics, Epigenetics and Environment in Cancer.

Mio Harachi, Kenta Masui, Webster K Cavenee, Paul S Mischel, Noriyuki Shibata.

  Metabolic reprogramming is an emerging hallmark of cancer and is driven by abnormalities of oncogenes and tumor suppressors. Accelerated metabolism causes cancer cell aggression through the dysregulation of rate-limiting metabolic enzymes as well as by facilitating the production of intermediary metabolites. However, the mechanisms by which a shift in the metabolic landscape reshapes the intracellular signaling to promote the survival of cancer cells remain to be clarified. Recent high-resolution mass spectrometry-based proteomic analyses have spotlighted that, unexpectedly, lysine residues of numerous cytosolic as well as nuclear proteins are acetylated and that this modification modulates protein activity, sublocalization and stability, with profound impact on cellular function. More importantly, cancer cells exploit acetylation as a post-translational protein for microenvironmental adaptation, nominating it as a means for dynamic modulation of the phenotypes of cancer cells at the interface between genetics and environments. The objectives of this review were to describe the functional implications of protein lysine acetylation in cancer biology by examining recent evidence that implicates oncogenic signaling as a strong driver of protein acetylation, which might be exploitable for novel therapeutic strategies against cancer.

Keywords:  epigenetics; mechanistic target of rapamycin (mTOR) complexes; metabolic reprogramming; microenvironment; protein acetylation

DOI:  https://doi.org/10.3390/metabo11040216
Cell Rep. 2021 Apr 27. pii: S2211-1247(21)00345-4. [Epub ahead of print]35(4): 109031

Leucine-sensing mechanism of leucyl-tRNA synthetase 1 for mTORC1 activation.

Sulhee Kim, Ina Yoon, Jonghyeon Son, Junga Park, Kibum Kim, Ji-Ho Lee, Sam-Yong Park, Beom Sik Kang, Jung Min Han, Kwang Yeon Hwang, Sunghoon Kim.

  Leucyl-tRNA synthetase 1 (LARS1) mediates activation of leucine-dependent mechanistic target of rapamycin complex 1 (mTORC1) as well as ligation of leucine to its cognate tRNAs, yet its mechanism of leucine sensing is poorly understood. Here we describe leucine binding-induced conformational changes of LARS1. We determine different crystal structures of LARS1 complexed with leucine, ATP, and a reaction intermediate analog, leucyl-sulfamoyl-adenylate (Leu-AMS), and find two distinct functional states of LARS1 for mTORC1 activation. Upon leucine binding to the synthetic site, H251 and R517 in the connective polypeptide and 50FPYPY54 in the catalytic domain change the hydrogen bond network, leading to conformational change in the C-terminal domain, correlating with RagD association. Leucine binding to LARS1 is increased in the presence of ATP, further augmenting leucine-dependent interaction of LARS1 and RagD. Thus, this work unveils the structural basis for leucine-dependent long-range communication between the catalytic and RagD-binding domains of LARS1 for mTORC1 activation.

Keywords:  X-ray crystallography; conformational change; leucine sensing; leucyl-tRNA synthetase 1; mechanistic target of rapamycin complex 1

DOI:  https://doi.org/10.1016/j.celrep.2021.109031
Behav Brain Res. 2021 Apr 25. pii: S0166-4328(21)00205-9. [Epub ahead of print] 113317

Rapamycin, but not minocycline, significantly alters ultrasonic vocalization behavior in C57Bl/6J pups in a flurothyl seizure model.

Samantha L Hodges, Paige D Womble, Eliesse M Kwok, Alyssa M Darner, Savannah S Senger, Matthew S Binder, Amanda M Faust, Siena M Condon, Suzanne O Nolan, Saul I Quintero, Joaquin N Lugo.

  Epilepsy is one of the most common neurological disorders, with individuals having an increased susceptibility of seizures in the first few years of life, making children at risk of developing a multitude of cognitive and behavioral comorbidities throughout development. The present study examined the role of PI3K/Akt/mTOR pathway activity and neuroinflammatory signaling in the development of autistic-like behavior following seizures in the neonatal period. Male and female C57BL/6 J mice were administered 3 flurothyl seizures on postnatal (PD) 10, followed by administration of minocycline, the mTOR inhibitor rapamycin, or a combined treatment of both therapeutics. On PD12, isolation-induced ultrasonic vocalizations (USVs) of mice were examined to determine the impact of seizures and treatment on communicative behaviors, a component of the autistic-like phenotype. Seizures on PD10 increased the quantity of USVs in female mice and reduced the amount of complex call types emitted in males compared to controls. Inhibition of mTOR with rapamycin significantly reduced the quantity and duration of USVs in both sexes. Changes in USVs were associated with increases in mTOR and astrocyte levels in male mice, however, three PD10 seizures did not result in enhanced proinflammatory cytokine expression in either sex. Beyond inhibition of mTOR activity by rapamycin, both therapeutics did not demonstrate beneficial effects. These findings emphasize the importance of differences that may exist across preclinical seizure models, as three flurothyl seizures did not induce as drastic of changes in mTOR activity or inflammation as observed in other rodent models.

Keywords:  Autism; Cell signaling; Cytokines; Early-life seizures; Epilepsy; Ultrasonic vocalizations

DOI:  https://doi.org/10.1016/j.bbr.2021.113317