bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2022‒09‒25
seven papers selected by
Marti Cadena Sandoval
Columbia University
  1. mTORC1 Activity in Psoriatic Lesions Is Mediated by Aberrant Regulation through the Tuberous Sclerosis Complex.
  2. LysM-positive neurons drive Tuberous Sclerosis Complex (TSC)-associated brain lesions.
  3. Exosome Release by Glucose Deprivation Is Important for the Viability of TSC-Null Cells.
  4. Renal Transcriptome and Metabolome in Mice with Principal Cell-Specific Ablation of the Tsc1 Gene: Derangements in Pathways Associated with Cell Metabolism, Growth and Acid Secretion.
  5. Possible Involvement of DNA Methylation in TSC1 Gene Expression in Neuroprotection Induced by Hypoxic Preconditioning.
  6. A review on role of metformin as a potential drug for epilepsy treatment and modulation of epileptogenesis.
  7. Co-ingestion of glutamine and leucine synergistically promotes mTORC1 activation.
  1. Cells. 2022 Sep 13. pii: 2847. [Epub ahead of print]11(18):
    mTORC1 Activity in Psoriatic Lesions Is Mediated by Aberrant Regulation through the Tuberous Sclerosis Complex.
    Antonio Ferreri, Victoria Lang, Roland Kaufmann, Claudia Buerger.
      In the basal, proliferative layer of healthy skin, the mTOR complex 1 (mTORC1) is activated, thus regulating proliferation while preventing differentiation. When cells leave the proliferative, basal compartment, mTORC1 signaling is turned off, which allows differentiation. Under inflammatory conditions, this switch is hijacked by cytokines and prevents proper differentiation. It is currently unknown how mTORC1 is regulated to mediate these effects on keratinocyte differentiation. In other tissues, mTORC1 activity is controlled through various pathways via the tuberous sclerosis complex (TSC). Thus, we investigated whether the TS complex is regulated by proinflammatory cytokines and contributes to the pathogenesis of psoriasis. TNF-α as well as IL-1β induced the phosphorylation of TSC2, especially on S939 via the PI3-K/AKT and MAPK pathway. Surprisingly, increased TSC2 phosphorylation could not be detected in psoriasis patients. Instead, TSC2 was strongly downregulated in lesional psoriatic skin compared to non-lesional skin of the same patients or healthy skin. In vitro inflammatory cytokines induced dissociation of TSC2 from the lysosome, followed by destabilization of the TS complex and degradation. Thus, we assume that in psoriasis, inflammatory cytokines induce strong TSC2 phosphorylation, which in turn leads to its degradation. Consequently, chronic mTORC1 activity impairs ordered keratinocyte differentiation and contributes to the phenotypical changes seen in the psoriatic epidermis.
    Keywords:  cytokines; inflammation; mTORC1; psoriasis; tuberous sclerosis complex
    DOI:  https://doi.org/10.3390/cells11182847
  2. Cell Signal. 2022 Sep 15. pii: S0898-6568(22)00230-3. [Epub ahead of print]100 110468
    LysM-positive neurons drive Tuberous Sclerosis Complex (TSC)-associated brain lesions.
    Jiahuan Zhang, Song Xu, Kangyan Liang, Xiong Cao, Zhixin Ye, Wenlan Huang, Xiaochun Bai, Yue Zhang.
      Mutations of Tsc1 or Tsc2 can lead to excessive activation of mTORC1 and cause Tuberous Sclerosis Complex (TSC), which is an autosomal dominant genetic disease prominently characterized by seizures, mental retardation and multiorgan hamartoma. In TSC, pathological changes in the central nervous system are the leading cause of death and disability. In decades, series of rodent models have been established by mutating Tsc1 or Tsc2 genes in diverse neural cell lineages to investigate the underlying cellular and molecular mechanisms, however, the cellular origin triggering neural pathological changes in TSC is undetermined. In this study, we generated a novel mouse model involving conditional deletion of Tsc1 in lysozyme 2 (Lyz2)-positive cells which replicated several features of brain lesions including epileptic seizures, megalencephaly, highly enlarged pS6-positive neurons and astrogliosis. In addition, we confirmed that bone marrow-derived myeloid cells including microglia with Tsc1 deficiency are not the decisive lineage in the cerebral pathologies in TSC. These histological assays in our murine model indicate an essential contribution of Lyz2-positive neurons to TSC progression. The Lyz2-positive neural population-specific onset of Tsc1 loss in murine postnatal brain might be the key to pathological phenotypes. Our findings thus provided evidences supporting new insights into the role of Lyz2-positive neurons in TSC events.
    Keywords:  Lyz2; Neuron; TSC model; Tuberous sclerosis complex 1; mTORC1
    DOI:  https://doi.org/10.1016/j.cellsig.2022.110468
  3. Cells. 2022 Sep 14. pii: 2862. [Epub ahead of print]11(18):
    Exosome Release by Glucose Deprivation Is Important for the Viability of TSC-Null Cells.
    Ji-Hyun Bae, Jong Hyun Kim.
      The control of exosome release is associated with numerous physiological and pathological activities, and that release is often indicative of health, disease, and environmental nutrient stress. Tuberous sclerosis complex (TSC) regulates the cell viability via the negative regulation of the mammalian target of rapamycin complex (mTORC1) during glucose deprivation. However, the mechanism by which viability of TSC-null cells is regulated by mTORC1 inhibition under glucose deprivation remains unclear. Here, we demonstrated that exosome release regulates cell death induced by glucose deprivation in TSC-null cells. The mTORC1 inhibition by rapamycin significantly increased the exosome biogenesis, exosome secretion, and cell viability in TSC-null cells. In addition, the increase in cell viability by mTORC1 inhibition was attenuated by two different types of inhibitors of exosome release under glucose deprivation. Taken together, we suggest that exosome release inhibition might be a novel way for regression of cell growth in TSC-null cells showing lack of cell death by mTORC1 inhibition.
    Keywords:  TSC; cell viability; exosome; glucose deprivation; mTORC1
    DOI:  https://doi.org/10.3390/cells11182862
  4. Int J Mol Sci. 2022 Sep 13. pii: 10601. [Epub ahead of print]23(18):
    Renal Transcriptome and Metabolome in Mice with Principal Cell-Specific Ablation of the Tsc1 Gene: Derangements in Pathways Associated with Cell Metabolism, Growth and Acid Secretion.
    Kamyar Zahedi, Sharon Barone, Marybeth Brooks, Tracy Murray Stewart, Robert A Casero, Manoocher Soleimani.
      Tuberous sclerosis complex (TSC) is caused by mutations in the hamartin (TSC1) or tuberin (TSC2) genes. Using a mouse model of TSC renal cystogenesis that we have previously described, the current studies delineate the metabolic changes in the kidney and their relation to alterations in renal gene expression. To accomplish this, we compared the metabolome and transcriptome of kidneys from 28-day-old wildtype (Wt) and principal cell-specific Tsc1 KO (Tsc1 KO) mice using targeted 1H nuclear magnetic resonance targeted metabolomic and RNA-seq analyses. The significant changes in the kidney metabolome of Tsc1 KO mice included reductions in the level of several amino acids and significant decreases in creatine, NADH, inosine, UDP-galactose, GTP and myo-inositol levels. These derangements may affect energy production and storage, signal transduction and synthetic pathways. The pertinent derangement in the transcriptome of Tsc1 KO mice was associated with increased collecting duct acid secretion, active cell division and the up-regulation of signaling pathways (e.g., MAPK and AKT/PI3K) that suppress the TSC2 GTPase-activating function. The combined renal metabolome and transcriptome alterations observed in these studies correlate with the unregulated growth and predominance of genotypically normal A-intercalated cells in the epithelium of renal cysts in Tsc1 KO mice.
    Keywords:  cystogenesis; hamartin; kidney; metabolome and transcriptome; principal cell; tuberous sclerosis complex
    DOI:  https://doi.org/10.3390/ijms231810601
  5. Oxid Med Cell Longev. 2022 ;2022 9306097
    Possible Involvement of DNA Methylation in TSC1 Gene Expression in Neuroprotection Induced by Hypoxic Preconditioning.
    Ruifang Qi, Yabin Xie, Xiaolu Zhang, Shuyuan Jiang, Xiaolei Liu, Wei Xie, Xiaoe Jia, Rengui Bade, You Liu, Kerui Gong, Wenjie Yang, Guanghui Guo, Kai Sun, Chunyang Zhang, Ruijuan Han, Guo Shao.
      Background: It has been reported that ischemia and ischemic preconditioning (IPC) have different effects on the expression of tuberous sclerosis complex 1 (TSC1), which may contribute to the tolerance to ischemia/hypoxia with the increase of autophagy. The mechanisms of TSC1 differential expression are still unclear under ischemia/IPC conditions in hippocampal Cornu Ammon 1 (CA1) and Cornu Ammon 3 (CA3) area neuronal cells. While we have shown that 5-Aza-CdR, a DNA methyltransferase inhibitor, can upregulate TSC1 and increase hypoxic tolerance by autophagy in vivo and in vitro, in this study, we examined whether DNA methylation was involved in the differential expression of TSC1 in the CA1 and CA3 regions induced by hypoxic preconditioning (HPC).Methods: Level of rapamycin (mTOR) autophagy, a downstream molecular pathway of TSC1/TSC2 complex, was detected in HPC mouse hippocampal CA1 and CA3 areas as well as in the HPC model of mouse hippocampal HT22 cells. DNA methylation level of TSC1 promoter (-720 bp~ -360 bp) was determined in CA1 and CA3 areas by bisulfite-modified DNA sequencing (BMDS). At the same time, autophagy was detected in HT22 cells transfected with GFP-LC3 plasmid. The role of TSC1 in neuroprotection was measured by cell viability and apoptosis, and the role of TSC1 in metabolism was checked by ATP assay and ROS assay in HT22 cells that overexpressed/knocked down TSC1.
    Results: HPC upregulated the expression of TSC1, downregulated the level of P-mTOR (Ser2448) and P-p70S6K (Thr389), and enhanced the activity of autophagy in both in vivo and in vitro. The increased expression of TSC1 in HPC may depend on its DNA hypomethylation in the promoter region in vivo. HPC also could reduce energy consumption in HT22 cells. Overexpression and knockdown of TSC1 can affect cell viability, cell apoptosis, and metabolism in HT22 cells exposed to hypoxia.
    Conclusion: TSC1 expression induced by HPC may relate to the downregulation of its DNA methylation level with the increase of autophagy and the decrease of energy demand.
    DOI:  https://doi.org/10.1155/2022/9306097
  6. Seizure. 2022 Sep 05. pii: S1059-1311(22)00196-0. [Epub ahead of print]101 253-261
    A review on role of metformin as a potential drug for epilepsy treatment and modulation of epileptogenesis.
    Ratnav Singh, Sudhir C Sarangi, Surender Singh, Manjari Tripathi.
      BACKGROUND: Available anti-seizure medications (ASMs) target the symptomatology of the disease rather than any significant disease/epileptogenesis modifying actions. There are critical concerns of drug resistance and seizure recurrence during epilepsy management. So, drug repurposing is evolving as a paradigm change in the quest for novel epilepsy treatment strategies. Metformin, a well-known anti-diabetic drug has shown multiple pieces of evidence of its potential antiepileptic action.OBJECTIVE: This review elucidates various mechanisms underlying the beneficial role of metformin in seizure control and modulation of the epileptogenesis process.
    METHODS: Preclinical and clinical evidence involving metformin's role in epilepsy and special conditions like tuberous sclerosis have been reviewed in this paper. The putative mechanisms of epileptogenesis modulation through the use of metformin are also summarised.
    RESULTS: This review found the efficacy of metformin in different seizure models including genetic knockout model, chemical induced, and kindling models. Only one clinical study of metformin in tuberous sclerosis has shown a reduction in seizure frequency and tumor volume compared to placebo. The suggested mechanisms of metformin relevant to epileptogenesis modulation mainly encompass AMPK activation, mTOR inhibition, protection against blood-brain-barrier disruption, inhibition of neuronal apoptosis, and reduction of oxidative stress. In addition to seizure protection, metformin has a potential role in attenuating adverse effects associated with epilepsy and ASMs such as cognition and memory impairment.
    CONCLUSION: Metformin has shown promising utility in epilepsy management and epileptogenesis modulation. The evidence in this review substantiates the need for a robust clinical trial to explore the efficacy and safety of metformin in persons with epilepsy.
    Keywords:  Drug repositioning; Epilepsy; Epileptogenesis; Metformin; mTOR
    DOI:  https://doi.org/10.1016/j.seizure.2022.09.003
  7. Sci Rep. 2022 Sep 23. 12(1): 15870
    Co-ingestion of glutamine and leucine synergistically promotes mTORC1 activation.
    Ryoji Yoshimura, Shuichi Nomura.
      Leucine (Leu) regulates protein synthesis and degradation via activation of mammalian target of rapamycin complex 1 (mTORC1). Glutamine (Gln) synergistically promotes mTORC1 activation with Leu via glutaminolysis and Leu absorption via an antiporter. However, Gln has also been shown to inhibit mTORC1 activity. To resolve this paradox, we aimed to elucidate the effects of Gln on Leu-mediated mTORC1 activation. We administered Leu, Gln, tryptophan, Leu + Gln, or Leu + tryptophan to mice after 24-h fasting. The mice were then administered puromycin to evaluate protein synthesis and the gastrocnemius muscle was harvested 30 min later. Phosphorylated eukaryotic initiation factor 4E-binding protein 1, 70-kDa ribosomal protein S6 kinase 1, and Unc-51 like kinase 1 levels were the highest in the Leu + Gln group and significantly increased compared with those in the control group; however, Gln alone did not increase the levels of phosphorylated proteins. No difference in glutamate dehydrogenase activity was observed between the groups. Leu concentrations in the gastrocnemius muscle were similar in the Leu-intake groups. Our study highlights a novel mechanism underlying the promotive effect of Gln on Leu-mediated mTORC1 activation, providing insights into the pathway through which amino acids regulate muscle protein metabolism.
    DOI:  https://doi.org/10.1038/s41598-022-20251-2
This page is being maintained by Thomas Krichel. It was last updated on 2022‒10‒17 at 13:43:18.