bims-tubesc 2022-02-27 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2022–02–27
eleven papers selected by

Tuber Brain Proportion Determines Epilepsy Onset in Children With Tuberous Sclerosis Complex.
Use of cannabidiol in the treatment of epilepsy.
Tuberous sclerosis in a 16 years old female: A case report.
Innocent until proven guilty? Longstanding atrial ectopy preceding cardiac rhabdomyoma diagnosis in tuberous sclerosis complex: a case report.
A critical period for development of cerebellar-mediated autism-relevant social behavior.
The Ragulator complex serves as a substrate-specific mTORC1 scaffold in regulating the nuclear translocation of transcription factor EB.
Identification of serum and glucocorticoid-regulated kinase 1 as a regulator of signal transducer and activator of transcription 3 signaling.
mTOR Signaling and Potential Therapeutic Targeting in Meningioma.
TSC/mTOR Pathway Mutation Associated Eosinophilic/Oncocytic Renal Neoplasms: A Heterogeneous Group of Tumors with Distinct Morphology, Immunohistochemical Profile, and Similar Genetic Background.
YAP regulates an SGK1/mTORC1/SREBP-dependent lipogenic program to support proliferation and tissue growth.
mTOR in the Mechanisms of Atherosclerosis and Cardiovascular Disease.

Pediatr Neurol. 2021 Dec 29. pii: S0887-8994(21)00278-2. [Epub ahead of print]129 39-45

Tuber Brain Proportion Determines Epilepsy Onset in Children With Tuberous Sclerosis Complex.

Fuyi Zhang, Lingling Xie, Xiaoya He, Xiaojie Song, Helin Zheng, Longlun Wang, Li Jiang.

   BACKGROUND: Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder characterized by epilepsy and structural abnormalities of the brain. Little research has been done to explore the relationship between the tuber brain proportion (TBP) and epilepsy. We investigated several quantitative cerebral lesions including TBP on magnetic resonance imaging (MRI) and their impact on the onset age, seizure mode, and antiseizure treatment effectiveness of epilepsy in children with TSC.
METHODS: We reviewed the clinical characteristics and MRI information of 44 children with TSC who had experienced epileptic seizures. Supratentorial tubers were quantitatively manually measured to calculate the TBP. The numbers of cortical/subcortical cyst-like tubers, diffuse lesions, subependymal nodules, and subependymal giant cell astrocytomas were also evaluated.
RESULTS: Twelve children (27.3%) had experienced infantile spasms, thirteen children (29.5%) had early-onset epilepsy, and twenty-seven patients (64.3%) had a significant reduction in the frequency of seizures after antiseizure treatments. The median TBP was 9.2%, and diffuse lesions (range: 0-2) and cortical cyst-like lesions (range: 0-17) were seen in seven and seventeen children, respectively. The values of TBP (P < 0.001), diffuse lesions (P < 0.001), and cortical cyst-like tubers (P < 0.001) were all associated with early-onset epilepsy. The values of TBP (P = 0.004) and cortical cyst-like tuber (P < 0.001) were associated with the occurrence of infantile spasms. The values of TBP (P = 0.01), diffuse lesions (P = 0.04), and cortical cyst-like tubers (P = 0.004) were negatively associated with the effectiveness of antiseizure treatments. There was no significant correlation between subcortical cyst-like tuber, subependymal nodule, subependymal giant cell astrocytoma, and epilepsy severity.
CONCLUSIONS: Increasing abnormality of the cerebral hemispheres, as shown by quantitative MRI analysis including TBP, cortical cyst-like tubers, and diffuse lesions, is associated with measures of more severe epilepsy due to TSC. The values of TBP demonstrate strong significance for early-onset epilepsy.

Keywords:  Epilepsy; Lesion burden; Magnetic resonance imaging; Severity; Tuber brain proportion; Tuberous sclerosis complex

DOI:  https://doi.org/10.1016/j.pediatrneurol.2021.12.012
Neurol Neurochir Pol. 2022 Feb 25.

Use of cannabidiol in the treatment of epilepsy.

Maria Mazurkiewicz-Bełdzińska, Marta Zawadzka.

   INTRODUCTION: Cannabis sativa has been cultivated for human use for about 5,000 years, and has likewise been used in the treatment of epilepsy for thousands of years.
STATE OF THE ART: Cannabidiol (CBD), which was isolated from cannabis sativa in 1940, has an anti-seizure effect and no psychoactive activity. Its effectiveness in reducing various types of seizures has been proven in animal seizure and epilepsy models. Recent randomised, placebo-controlled trials have confirmed its effectiveness in patients with drug-resistant epilepsy.
CLINICAL IMPLICATIONS: The aim of this position paper was to present the specific mechanism of CBD's anti-seizure action and current indications for CBD's use in epilepsy. The only cannabis-derived drug that has successfully passed clinical trials and has obtained United States Food and Drug Administration and European Medicines Agency approval for epilepsy is Epidiolex®. This paper presents the outcomes of the completed clinical trials with the use of this drug.
FUTURE DIRECTIONS: CBD may be an effective drug in drug-resistant epilepsy, particularly in Dravet Syndrome, Lennox- Gastaut Syndrome and seizures associated with tuberous sclerosis complex. Additional randomised, placebo-controlled studies with CBD are needed.

Keywords:  Dravet Syndrome; Lennox-Gastaut Syndrome; cannabidiol; drug-resistant epilepsy; tuberous sclerosis

DOI:  https://doi.org/10.5603/PJNNS.a2022.0020
Ann Med Surg (Lond). 2022 Feb;74 103331

Tuberous sclerosis in a 16 years old female: A case report.

Fatima Ashfaq, Saurab Karki, Hajra Ishfaq, Sunil Shahi, Manoj Khadka.

   Introduction: Tuberous sclerosis complex (TSC) is an uncommon multisystem disorder that can affect the lungs, skin, kidneys, and brain. The study highlights the importance of genetic and clinical diagnostic criteria in identifying this rare condition and the role of surveillance in preventing complications.
Case presentation: Herein, we report a case of 16 years old female presenting with right flank pain, hematuria, hypopigmented macule over the back, ash leaf spots over the right upper and lower limb, and a palpable mass over the right lumbar region. Laboratory tests showed low hemoglobin with plenty of red blood cells in urine. She was admitted for symptomatic management of pain and blood transfusion was done to manage anemia. After a diagnostic workup for tuberous sclerosis, she was diagnosed with the condition and is under regular follow-up.
Clinical discussion: Tuberous sclerosis complex is one of the neurocutaneous syndromes, diagnosed based on the genetic or clinical diagnostic criteria as per the second International Tuberous Sclerosis Complex Consensus Conference 2012, which have been updated in 2021 with no changes in genetic diagnostic criteria and slight changes in clinical diagnostic criteria. After diagnosis, along with the management, surveillance is also crucial.
Conclusion: Tuberous sclerosis runs a progressive course and can lead to various complications. Thus, early diagnosis with the help of genetic and clinical diagnostic criteria is important along with regular surveillance of different body systems to prevent debilitating complications.

Keywords:  Case report; Hematuria; Tuberous sclerosis

DOI:  https://doi.org/10.1016/j.amsu.2022.103331
Eur Heart J Case Rep. 2022 Feb;6(2): ytac068

Innocent until proven guilty? Longstanding atrial ectopy preceding cardiac rhabdomyoma diagnosis in tuberous sclerosis complex: a case report.

Alison J Howell, Rachel D Vanderlaan, Christopher Z Lam, Katie L Losenno, Juan Putra, Olivier Villemain.

   Background: Cardiac rhabdomyoma are the most common cardiac tumour in childhood and are associated with tuberous sclerosis complex (TSC) up to 96% of infant cases. They classically manifest in the foetal and neonatal period, undergo spontaneous regression in the first years of life and are associated with arrhythmia in part due to interruption of normal conduction pathways by the tumour.
Case summary: We present a case of a 3-year-old boy with a long-standing history of atrial ectopy who was incidentally found to be in atrial flutter due to a new, rapidly growing cardiac rhabdomyoma impacting ventricular function. The boy was later confirmed with further investigation and TSC1 gene test to have TSC.
Discussion: Cardiac Rhabdomyoma does not always present in the infantile period. Any ongoing or new cardiac concern in patient with TSC, even if seemingly minor, should warrant more frequent cardiac evaluation and investigation.

Keywords:  Atrial flutter; Cardiac rhabdomyoma; Case report; Paediatric cardiology; Tuberous sclerosis complex

DOI:  https://doi.org/10.1093/ehjcr/ytac068
J Neurosci. 2022 Feb 21. pii: JN-RM-1230-21. [Epub ahead of print]

A critical period for development of cerebellar-mediated autism-relevant social behavior.

Jennifer M Gibson, Cleone P Howland, Chongyu Ren, Cyrena Howland, Alexandra Vernino, Peter T Tsai.

The cerebellum has been increasingly implicated in Autism Spectrum Disorder (ASD) with many ASD-linked genes impacting both cerebellar function and development. However, the precise timing and critical periods of when abnormal cerebellar neurodevelopment contributes to ASD-relevant behaviors remains poorly understood. In this study, we identify a critical period for the development of ASD-relevant behaviors in a cerebellar male mouse model of Tuberous Sclerosis Complex (TSC), by using the mechanistic target of rapamycin (mTOR) inhibitor, rapamycin, to pharmacologically inhibit dysregulated downstream signaling. We find independent critical periods during which abnormal ASD-relevant behaviors develop for the two core ASD diagnostic criteria - social impairments and behavioral flexibility - and delineate an anatomical, physiological, and behavioral framework. These findings not only further our understanding of the genetic mechanisms underlying the timing of ASD-relevant behaviors but also have the capacity to inform potential therapies to optimize treatment interventions.SIGNIFICANCE STATEMENTNo targeted treatments currently exist for ASD. This complex developmental disorder has established links to genetic and circuit aberrations, yet the precise timing and coordination of these underlying mechanisms that contribute to the spectrum of physiological and behavioral abnormalities remains unclear. Cerebellar pathology is consistently seen in ASD individuals; therefore, we sought to identify the specific windows for cerebellar involvement in the development of ASD-relevant behaviors. Using pharmacologic treatment paradigms, we outline distinct critical periods of developmental vulnerability for ASD-relevant social and inflexible behaviors. From this study, we posit a refined window of time during which ASD symptoms develop that will inform therapeutic timing.

DOI: https://doi.org/10.1523/JNEUROSCI.1230-21.2021
J Biol Chem. 2022 Feb 17. pii: S0021-9258(22)00184-3. [Epub ahead of print] 101744

The Ragulator complex serves as a substrate-specific mTORC1 scaffold in regulating the nuclear translocation of transcription factor EB.

Tetsuya Kimura, Yoshitomo Hayama, Daisuke Okuzaki, Shigeyuki Nada, Masato Okada.

  The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway is activated by intracellular nutritional sufficiency and extracellular growth signals. It has been reported that mTORC1 acts as a hub that integrates these inputs to orchestrate a number of cellular responses, including translation, nucleotide synthesis, lipid synthesis, and lysosome biogenesis. However, little is known about specific control of mTORC1 signaling downstream of this complex. Here, we demonstrate that Ragulator, a heteropentameric protein complex required for mTORC1 activation in response to amino acids, is critical for inhibiting the nuclear translocation of transcription factor EB (TFEB). We established a unique RAW264.7 clone that lacked Ragulator but retained total mTORC1 activity. In a nutrition-sufficient state, the nuclear translocation of TFEB was markedly enhanced in the clone despite total mTORC1 kinase activity. In addition, as a cellular phenotype, the number of lysosomes was increased by ten-fold in the Ragulator-deficient clone compared to that of control cells. These findings indicate that mTORC1 essentially requires the Ragulator complex for regulating the subcellular distribution of TFEB. Our findings also suggest that other scaffold proteins may be associated with mTORC1 for the specific regulation of downstream signaling.

Keywords:  Ragulator; lysosome; mammalian target of rapamycin (mTOR); nuclear translocation; scaffold protein; transcription factor EB

DOI:  https://doi.org/10.1016/j.jbc.2022.101744
Exp Cell Res. 2022 Feb 21. pii: S0014-4827(22)00072-6. [Epub ahead of print] 113079

Identification of serum and glucocorticoid-regulated kinase 1 as a regulator of signal transducer and activator of transcription 3 signaling.

Toshihiro Araki, Yuuki Watanabe, Yusuke Okada, Hisashi Murakami, Naohisa Ogo, Akira Asai.

  Signal transducer and activator of transcription 3 (STAT3) plays key roles in cancer cell proliferation, invasion, and immunosuppression. In many human cancer cells, STAT3 is hyperactivated, which leads to tumor progression and drug resistance, and therefore STAT3 and its modulators are considered effective drug targets. However, the complex regulatory mechanisms of STAT3 have made it difficult to develop potent anticancer drugs that suppress its activity. Here, we report serum and glucocorticoid-regulated kinase 1 (SGK1) as a novel regulator of STAT3 signaling and an effective target for combination therapy with Janus kinase (JAK) inhibitors. We screened small molecules using a gain-of-function mutant of STAT3 resistant to JAK inhibition and found that an SGK1 inhibitor suppressed the constitutive activation of STAT3. Importantly, our results revealed that SGK1 also mediated the activation of wild-type STAT3. Further examination suggested that the tuberous sclerosis complex 2 and mammalian target of rapamycin signaling pathway were involved in STAT3 activation by SGK1. Finally, we demonstrated that SGK1 inhibition enhanced the inhibitory effect of a JAK inhibitor on STAT3 phosphorylation and cancer cell proliferation. Our findings provide new insights into the molecular mechanisms of STAT3 activation and suggest SGK1 as a potential target for STAT3-targeted combination cancer therapy.

Keywords:  JAK; SGK1; STAT3; Small molecule; TSC2

DOI:  https://doi.org/10.1016/j.yexcr.2022.113079
Int J Mol Sci. 2022 Feb 10. pii: 1978. [Epub ahead of print]23(4):

mTOR Signaling and Potential Therapeutic Targeting in Meningioma.

Benjamin Pinker, Anna-Maria Barciszewska.

  Meningiomas are the most frequent primary tumors arising in the central nervous system. They typically follow a benign course, with an excellent prognosis for grade I lesions through surgical intervention. Although radiotherapy is a good option for recurrent, progressive, or inoperable tumors, alternative treatments are very limited. mTOR is a protein complex with increasing therapeutical potential as a target in cancer. The current understanding of the mTOR pathway heavily involves it in the development of meningioma. Its activation is strongly dependent on PI3K/Akt signaling and the merlin protein. Both factors are commonly defective in meningioma cells, which indicates their likely function in tumor growth. Furthermore, regarding molecular tumorigenesis, the kinase activity of the mTORC1 complex inhibits many components of the autophagosome, such as the ULK1 or Beclin complexes. mTOR contributes to redox homeostasis, a vital component of neoplasia. Recent clinical trials have investigated novel chemotherapeutic agents for mTOR inhibition, showing promising results in resistant or recurrent meningiomas.

Keywords:  everolimus; lycopene; mTOR; macroautophagy; meningioma; redox homeostasis; vistusertib

DOI:  https://doi.org/10.3390/ijms23041978
Biomedicines. 2022 Jan 29. pii: 322. [Epub ahead of print]10(2):

TSC/mTOR Pathway Mutation Associated Eosinophilic/Oncocytic Renal Neoplasms: A Heterogeneous Group of Tumors with Distinct Morphology, Immunohistochemical Profile, and Similar Genetic Background.

Kristyna Pivovarcikova, Reza Alaghehbandan, Tomas Vanecek, Riuko Ohashi, Tomas Pitra, Ondrej Hes.

  A number of recently described renal tumor entities share an eosinophilic/oncocytic morphology, somewhat solid architectural growth pattern, and tendency to present as low-stage tumors. The vast majority of such tumors follow a non-aggressive clinical behavior. In this review, we discuss the morphological, immunohistochemical, and molecular genetic profiles of the three most recent novel/emerging renal entities associated with TSC/mTOR pathway mutations. These are eosinophilic solid and cystic renal cell carcinoma, eosinophilic vacuolated tumors, and low-grade oncocytic tumors, which belong to a heterogeneous group of renal tumors, demonstrating mostly solid architecture, eosinophilic/oncocytic cytoplasm, and overlapping morphological and immunohistochemical features between renal oncocytoma and chromophobe renal cell carcinoma. All three tumors also share a molecular genetic background with mutations in the mTORC1 pathway (TSC1/TSC2/mTOR/RHEB). Despite the common genetic background, it appears that the tumors with TSC/mTOR mutations represent a diverse group of distinct renal neoplasms.

Keywords:  ESC; EVT; LOT; chromophobe; eosinophilic; kidney; mTOR; oncocytic; renal; tumor

DOI:  https://doi.org/10.3390/biomedicines10020322
Dev Cell. 2022 Feb 15. pii: S1534-5807(22)00070-3. [Epub ahead of print]

YAP regulates an SGK1/mTORC1/SREBP-dependent lipogenic program to support proliferation and tissue growth.

Srimayee Vaidyanathan, Talhah M Salmi, Rasan M Sathiqu, Malcolm J McConville, Andrew G Cox, Kristin K Brown.

  The coordinated regulation of growth control and metabolic pathways is required to meet the energetic and biosynthetic demands associated with proliferation. Emerging evidence suggests that the Hippo pathway effector Yes-associated protein 1 (YAP) reprograms cellular metabolism to meet the anabolic demands of growth, although the mechanisms involved are poorly understood. Here, we demonstrate that YAP co-opts the sterol regulatory element-binding protein (SREBP)-dependent lipogenic program to facilitate proliferation and tissue growth. Mechanistically, YAP stimulates de novo lipogenesis via mechanistic target of rapamcyin (mTOR) complex 1 (mTORC1) signaling and subsequent activation of SREBP. Importantly, YAP-dependent regulation of serum- and glucocorticoid-regulated kinase 1 (SGK1) is required to activate mTORC1/SREBP and stimulate de novo lipogenesis. We also find that the SREBP target genes fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD) are conditionally required to support YAP-dependent proliferation and tissue growth. These studies reveal that de novo lipogenesis is a metabolic vulnerability that can be targeted to disrupt YAP-dependent proliferation and tissue growth.

Keywords:  SGK1; SREBP; YAP; cell metabolism; growth; lipogenesis; mTORC1; proliferation

DOI:  https://doi.org/10.1016/j.devcel.2022.02.004
Discov Med. 2021 May-Jun;31(164):31(164): 129-140

mTOR in the Mechanisms of Atherosclerosis and Cardiovascular Disease.

Zhe Liu, Yuxin Fan, Zhongliang Zhang, Yudong Fang, Xin Cheng, Qintong Yang, Jingwen Liu, Jun Xie.

mTOR (the mammalian target of rapamycin) is a serine/threonine kinase that can regulate a variety of signaling pathways, including cell growth, proliferation, and apoptosis. mTOR can regulate the proliferation and migration of endothelial cells and smooth muscle cells during the occurrence and progression of atherosclerosis. By inhibiting or activating mTOR at different time points, atherosclerotic vulnerable plaques can be stabilized and the occurrence and progression of atherosclerosis can be impeded. The mTOR signaling pathway plays a multifaceted role in the progression of atherosclerosis. mTOR and its interactions with molecular targets in the mechanisms of atherosclerosis and cardiovascular diseases are reviewed in this article, taking into consideration their potential of opening up novel therapeutic avenues.