bims-tubesc 2022-11-06 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2022–11–06
eight papers selected by

Genetic and Environmental Contributions to Autism Spectrum Disorder Through Mechanistic Target of Rapamycin.
[Clinical characteristics and genetic analysis of a Chinese pedigree affected with tuberous sclerosis complex].
Clinical seizure semiology is subtle and identification of seizures by parents unreliable in infants with tuberous sclerosis complex.
Ca2+/Calmodulin induces translocation of membrane-associated TSC2 to the nucleus where it suppresses CYP24A1 expression.
Machine learning and statistic analysis to predict drug treatment outcome in pediatric epilepsy patients with tuberous sclerosis complex.
Disruption of mTORC1 rescues neuronal overgrowth and synapse function dysregulated by Pten loss.
Challenges and Emerging Opportunities for Targeting mTOR in Cancer.
Phosphoproteomic Analysis Defines BABAM1 as mTORC2 Downstream Effector Promoting DNA Damage Response in Glioblastoma Cells.

Biol Psychiatry Glob Open Sci. 2022 Apr;2(2): 95-105

Genetic and Environmental Contributions to Autism Spectrum Disorder Through Mechanistic Target of Rapamycin.

Atsushi Sato, Kazutaka Ikeda.

  Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects an individual's reciprocal social interaction and communication ability. Numerous genetic and environmental conditions are associated with ASD, including tuberous sclerosis complex, phosphatase and tensin homolog hamartoma tumor syndrome, fragile X syndrome, and neurofibromatosis 1. The pathogenic molecular mechanisms of these diseases are integrated into the hyperactivation of mTORC1 (mechanistic target of rapamycin complex 1). Rodent models of these diseases have shown high mTORC1 activity in the brain and ASD-related behavioral deficits, which were reversed by the mTORC1 inhibitor rapamycin. Environmental stress can also affect this signaling pathway. In utero exposure to valproate caused ASD in offspring and enhanced mTORC1 activity in the brain, which was sensitive to mTORC1 inhibition. mTORC1 is a signaling hub for diverse cellular functions, including protein synthesis, through the phosphorylation of its targets, such as ribosomal protein S6 kinases. Metabotropic glutamate receptor 5-mediated synaptic function is also affected by the dysregulation of mTORC1 activity, such as in fragile X syndrome and tuberous sclerosis complex. Reversing these downstream changes that are associated with mTORC1 activation normalizes behavioral defects in rodents. Despite abundant preclinical evidence, few clinical studies have investigated the treatment of ASD and cognitive deficits. Therapeutics other than mTORC1 inhibitors failed to show efficacy in fragile X syndrome and neurofibromatosis 1. mTORC1 inhibitors have been tested mainly in tuberous sclerosis complex, and their effects on ASD and neuropsychological deficits are promising. mTORC1 is a promising target for the pharmacological treatment of ASD associated with mTORC1 activation.

Keywords:  Animal models; Autism spectrum disorder; Autophagy; Mechanistic target of rapamycin; Metabotropic glutamate receptor; Protein synthesis

DOI:  https://doi.org/10.1016/j.bpsgos.2021.08.005
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2022 Nov 10. 39(11): 1238-1242

[Clinical characteristics and genetic analysis of a Chinese pedigree affected with tuberous sclerosis complex].

Li Chen, Gang Li, Chen Zhang, Meng Jiao, Xiaoyan Li.

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with tuberous sclerosis complex (TSC).
METHODS: The TSC1 and TSC2 genes were sequenced. Candidate variant was verified by Sanger sequencing of the proband and her family members. Pathogenicity of the variant was predicted based on the American College of Medical Genetics and Genomics (ACMG) guidelines.
RESULTS: The proband was found to harbor a heterozygous c.52delC frameshift variant of the TSC2 gene, which may result in synthesis of amino acid chain starting from the 18th amino acid Leu and terminating at the 28th amino acid (p.Leu18CysfsTer28). The variant was unreported in the public database. Mutation Taster software predicted that the variant is harmful. Both parents of the proband were of the wild type, suggesting that the variant has occurred de novo. Based on the ACMG guidelines, the variant was predicted to be likely pathogenic (PVS1 +PM2).
CONCLUSION: A novel pathogenic variant of the TSC2 gene c.52delC (p.Leu18CysfsTer28) was identified, which has enriched the mutational spectrum of TSC2 and provided a basis for genetic counseling for this pedigree.

DOI: https://doi.org/10.3760/cma.j.cn511374-20211122-00928
Epilepsia. 2022 Nov 01.

Clinical seizure semiology is subtle and identification of seizures by parents unreliable in infants with tuberous sclerosis complex.

Matthew Lynch, Kirsty Smith, Kate Riney.

   OBJECTIVE: The objectives of this study were to assess the accuracy of parental seizure detection in infants with antenatally diagnosed tuberous sclerosis complex (TSC), and to document the total seizure burden (clinical and subclinical) in those patients who met criteria for prolonged EEG recording.
METHODS: Consecutive infants at a single institution with antenatally diagnosed TSC who met criteria for prolonged video-EEG (vEEG) were recruited to this study. The vEEG data was reviewed and when a seizure was identified on EEG, the video and audio recording was assessed for evidence of clinical seizure and if present whether there was evidence of parent seizure identification.
RESULTS: Nine infants were enrolled, for whom 674 focal seizures were identified in 8/9 patients across 24 prolonged vEEG recordings, with vEEG total duration 634 hours 49 minutes (average seizure frequency of 1 focal seizure/hour). Only 220/674 (32.6%) were clinical seizures, 395/674 (58.6%) were subclinical seizures and 59/674 seizures were unable to be classified. Only 63/220 (28.6%) clinical seizures were identified by parents, with 157/220 (71.4%) not identified. Thirty clusters of epileptic spasms were detected in 1 patient. At least one clinical epileptic spasm occurred in 2/30 (6.7%) clusters, 24/30 (80%) clusters of epileptic spasms were electrographic only, and classification was uncertain for 4/30 (13.3%) clusters. No clinical epileptic spasms were detected by parents. Clinical seizure frequency was significantly under-estimated by parents in all patients.
SIGNIFICANCE: This study demonstrates that in TSC infants meeting criteria for prolonged vEEG, that 1) parents significantly under-identify total clinical seizure count, 2) parents fail to identify epileptic spasms and 3) that seizure frequency is high. This highlights that epilepsy treatment decisions should not be solely based on parental clinical seizure identification. Prolonged vEEG monitoring may have an important role in the routine epilepsy care of TSC infants, as demonstrating undetected high clinical seizure frequency may allow improved epilepsy management decisions.

Keywords:  EEG; epilepsy; fetal; subclinical seizure; tuberous sclerosis

DOI:  https://doi.org/10.1111/epi.17454
Biosci Biotechnol Biochem. 2022 Nov 04. pii: zbac174. [Epub ahead of print]

Ca2+/Calmodulin induces translocation of membrane-associated TSC2 to the nucleus where it suppresses CYP24A1 expression.

Machiko Kazami, Tomoya Sakamoto, Tsukasa Suzuki, Hirofumi Inoue, Hayato Kato, Ken-Ichi Kobayashi, Tadahiro Tadokoro, Yuji Yamamoto.

  Tuberous sclerosis complex 2 (TSC2) is a tumor-suppressor protein. A loss of TSC2 function induces hyperactivation of mechanistic target of rapamycin (mTOR). The C-terminal region of TSC2 contains a calmodulin (CaM) binding region and the CaM-TSC2 interaction contributes to proper mTOR activity. However, other downstream signaling pathways/effectors activated by the CaM-TSC2 complex have not been fully elucidated. In this study, we found that activation of Ca2+/CaM signaling resulted in the translocation of membrane-associated TSC2 to the nucleus and suppressed the transcriptional activity of the vitamin D receptor (VDR). TSC2 was released from the membrane in an activated CaM-dependent state in rat brain and HeLa cells. It subsequently formed a transcriptional complex to partially suppress the transcription of CYP24A1, a well-known VDR target gene. These data suggest, in part, that TSC2 attenuates VDR-associated transcriptional regulation via Ca2+/CaM signaling.

Keywords:   CYP24A1 ; CaM; TSC2; Translocation; Vitamin D metabolism

DOI:  https://doi.org/10.1093/bbb/zbac174
Epilepsy Res. 2022 Oct 20. pii: S0920-1211(22)00191-7. [Epub ahead of print]188 107040

Machine learning and statistic analysis to predict drug treatment outcome in pediatric epilepsy patients with tuberous sclerosis complex.

Xia Zhao, Dian Jiang, Zhanqi Hu, Jun Yang, Dong Liang, Bixia Yuan, Rongbo Lin, Haifeng Wang, Jianxiang Liao, Cailei Zhao.

   OBJECTIVES: We aimed to investigate the association between multi-modality features and epilepsy drug treatment outcomes and propose a machine learning model to predict epilepsy drug treatment outcomes with multi-modality features.
METHODS: This retrospective study consecutively enrolled 103 epilepsy children with rare TSC. Multi-modality data were used to characterize risk factors for epilepsy drug treatment outcome of TSC, including clinical data, TSC1, and TSC2 genes test results, magnetic resonance imaging (MRI), computerized tomography (CT), and electroencephalogram (EEG). Three common feature selection methods and six common machine learning models were used to find the best combination of feature selection and machine learning model for epilepsy drug treatment outcomes prediction with multi-modality features for TSC clinical application.
RESULTS: The analysis of variance based on selected 35 features combined with multilayer perceptron (MLP) model achieved the best area-under-curve score (AUC) of 0.812 (±0.005). Infantile spasms, EEG discharge type, epileptiform discharge in the right frontal area of EEG, drug-resistant epilepsy, gene mutation type, and type II lesions were positively correlated with drug treatment outcome. Age of onset and age of visiting doctors were negatively correlated with drug treatment outcome (p < 0.05). Our machine learning results found that among MRI features, lesion type is the most important in the outcome prediction, followed by location and quantity.
CONCLUSION: We developed and validated an effective prediction model for epilepsy drug treatment outcomes of TSC. Our results suggested that multi-modality features analysis and MLP-based machine learning can predict epilepsy drug treatment outcomes of TSC.

Keywords:  Children; Epilepsy; Machine learning; Outcome prediction; Statistical analysis; Tuberous sclerosis complex

DOI:  https://doi.org/10.1016/j.eplepsyres.2022.107040
Cell Rep. 2022 Nov 01. pii: S2211-1247(22)01435-8. [Epub ahead of print]41(5): 111574

Disruption of mTORC1 rescues neuronal overgrowth and synapse function dysregulated by Pten loss.

Kamran Tariq, Erin Cullen, Stephanie A Getz, Andie K S Conching, Andrew R Goyette, Mackenzi L Prina, Wei Wang, Meijie Li, Matthew C Weston, Bryan W Luikart.

  Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of AKT/mTOR signaling pathway. Mutations in PTEN are found in patients with autism, epilepsy, or macrocephaly. In mouse models, Pten loss results in neuronal hypertrophy, hyperexcitability, seizures, and ASD-like behaviors. The underlying molecular mechanisms of these phenotypes are not well delineated. We determined which of the Pten loss-driven aberrations in neuronal form and function are orchestrated by downstream mTOR complex 1 (mTORC1). Rapamycin-mediated inhibition of mTORC1 prevented increase in soma size, migration, spine density, and dendritic overgrowth in Pten knockout dentate gyrus granule neurons. Genetic knockout of Raptor to disrupt mTORC1 complex formation blocked Pten loss-mediated neuronal hypertrophy. Electrophysiological recordings revealed that genetic disruption of mTORC1 rescued Pten loss-mediated increase in excitatory synaptic transmission. We have identified an essential role for mTORC1 in orchestrating Pten loss-driven neuronal hypertrophy and synapse formation.

Keywords:  CP: Cell biology; CP: Neuroscience; PTEN; Raptor; autism; dendrite; mTOR; rapamycin; synapse

DOI:  https://doi.org/10.1016/j.celrep.2022.111574
Cancer Res. 2022 Nov 02. 82(21): 3884-3887

Challenges and Emerging Opportunities for Targeting mTOR in Cancer.

Kris C Wood, J Silvio Gutkind.

The mechanistic target of rapamycin (mTOR) plays a key role in normal and malignant cell growth. However, pharmacologic targeting of mTOR in cancer has shown little clinical benefit, in spite of aberrant hyperactivation of mTOR in most solid tumors. Here, we discuss possible reasons for the reduced clinical efficacy of mTOR inhibition and highlight lessons learned from recent combination clinical trials and approved indications of mTOR inhibitors in cancer. We also discuss how the emerging systems level understanding of mTOR signaling in cancer can be exploited for the clinical development of novel multimodal precision targeted therapies and immunotherapies aimed at achieving tumor remission.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0602
J Proteome Res. 2022 Oct 31.

Phosphoproteomic Analysis Defines BABAM1 as mTORC2 Downstream Effector Promoting DNA Damage Response in Glioblastoma Cells.

Nuttiya Kalpongnukul, Rungnapa Bootsri, Piriya Wongkongkathep, Pornchai Kaewsapsak, Chaiyaboot Ariyachet, Trairak Pisitkun, Naphat Chantaravisoot.

  Glioblastoma (GBM) is a devastating primary brain cancer with a poor prognosis. GBM is associated with an abnormal mechanistic target of rapamycin (mTOR) signaling pathway, consisting of two distinct kinase complexes: mTORC1 and mTORC2. The complexes play critical roles in cell proliferation, survival, migration, metabolism, and DNA damage response. This study investigated the aberrant mTORC2 signaling pathway in GBM cells by performing quantitative phosphoproteomic analysis of U87MG cells under different drug treatment conditions. Interestingly, a functional analysis of phosphoproteome revealed that mTORC2 inhibition might be involved in double-strand break (DSB) repair. We further characterized the relationship between mTORC2 and BRISC and BRCA1-A complex member 1 (BABAM1). We demonstrated that pBABAM1 at Ser29 is regulated by mTORC2 to initiate DNA damage response, contributing to DNA repair and cancer cell survival. Accordingly, the inactivation of mTORC2 significantly ablated pBABAM1 (Ser29), reduced DNA repair activities in the nucleus, and promoted apoptosis of the cancer cells. Furthermore, we also recognized that histone H2AX phosphorylation at Ser139 (γH2AX) could be controlled by mTORC2 to repair the DNA. These results provided a better understanding of the mTORC2 function in oncogenic DNA damage response and might lead to specific mTORC2 treatments for brain cancer patients in the future.

Keywords:  BABAM1; DNA damage response; glioblastoma; mTORC2; phosphoproteomics

DOI:  https://doi.org/10.1021/acs.jproteome.2c00240