bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2021‒12‒12
eleven papers selected by
Marti Cadena Sandoval
metabolic-signalling.eu
  1. Risk Factors Associated with Refractory Epilepsy in Patients with Tuberous Sclerosis Complex: A Systematic Review.
  2. Identifying the temporal electrophysiological and molecular changes that contribute to TSC-associated epileptogenesis.
  3. Renal Neoplasia in Polycystic Kidney Disease: An Assessment of Tuberous Sclerosis Complex-associated Renal Neoplasia and PKD1/TSC2 Contiguous Gene Deletion Syndrome.
  4. Vagus nerve stimulation for drug-resistant epilepsy induced by tuberous sclerosis complex.
  5. Genetics and optical coherence tomography features in a child with an achromatic retinal patch.
  6. A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci.
  7. An unexpected tumor suppressor role of SQSTM1/p62 in liver tumorigenesis.
  8. The mTOR-lysosome axis at the centre of ageing.
  9. The Cross Talk Between p53 and mTOR Pathways in Response to Physiological and Genotoxic Stresses.
  10. Exercise increases phosphorylation of the putative mTORC2 activity readout NDRG1 in human skeletal muscle.
  11. TTK inhibition increases cisplatin sensitivity in high-grade serous ovarian carcinoma through the mTOR/autophagy pathway.
  1. J Clin Med. 2021 Nov 24. pii: 5495. [Epub ahead of print]10(23):
    Risk Factors Associated with Refractory Epilepsy in Patients with Tuberous Sclerosis Complex: A Systematic Review.
    Dominika Miszewska, Monika Sugalska, Sergiusz Jóźwiak.
      BACKGROUND: Epilepsy affects 70-90% of patients with tuberous sclerosis complex (TSC). In one-third of them, the seizures become refractory to treatment. Drug-resistant epilepsy (DRE) carries a significant educational, social, cognitive, and economic burden. Therefore, determining risk factors that increase the odds of refractory seizures is needed. We reviewed current data on risk factors associated with DRE in patients with tuberous sclerosis.METHODS: The review was performed according to the PRISMA guidelines. Embase, Cochrane Library, MEDLINE, and ClinicalTrial.gov databases were searched. Only full-text journal articles on patients with TSC which defined risk factors related to DRE were included.
    RESULTS: Twenty articles were identified, with a cohort size between 6 and 1546. Seven studies were prospective. Three factors appear to significantly increase DRE risk: TSC2 mutation, infantile spasms, and a high number of cortical tubers.
    CONCLUSIONS: A proper MRI and EEG monitoring, along with genetic testing, and close observation of individuals with early onset of seizures, allow identification of the patients at risk of DRE.
    Keywords:  drug resistant epilepsy; refractory seizures; risk factors; tuberous sclerosis complex
    DOI:  https://doi.org/10.3390/jcm10235495
  2. JCI Insight. 2021 Dec 08. pii: e150120. [Epub ahead of print]6(23):
    Identifying the temporal electrophysiological and molecular changes that contribute to TSC-associated epileptogenesis.
    Linda Mc Koene, Eva Niggl, Ilse Wallaard, Martina Proietti-Onori, Diana C Rotaru, Ype Elgersma.
      Tuberous sclerosis complex (TSC), caused by heterozygous mutations in TSC1 or TSC2, frequently results in intractable epilepsy. Here, we made use of an inducible Tsc1-knockout mouse model, allowing us to study electrophysiological and molecular changes of Tsc1-induced epileptogenesis over time. We recorded from pyramidal neurons in the hippocampus and somatosensory cortex (L2/L3) and combined this with an analysis of transcriptome changes during epileptogenesis. Deletion of Tsc1 resulted in hippocampus-specific changes in excitability and adaptation, which emerged before seizure onset and progressed over time. All phenotypes were rescued after early treatment with rapamycin, an mTOR inhibitor. Later in epileptogenesis, we observed a hippocampal increase of excitation-to-inhibition ratio. These cellular changes were accompanied by dramatic transcriptional changes, especially after seizure onset. Most of these changes were rescued upon rapamycin treatment. Of the genes encoding ion channels or belonging to the Gene Ontology term action potential, 27 were differentially expressed just before seizure onset, suggesting a potential driving role in epileptogenesis. Our data highlight the complex changes driving epileptogenesis in TSC, including the changed expression of multiple ion channels. Our study emphasizes inhibition of the TSC/mTOR signaling pathway as a promising therapeutic approach to target epilepsy in patients with TSC.
    Keywords:  Epilepsy; Ion channels; Neuroscience; Transcription
    DOI:  https://doi.org/10.1172/jci.insight.150120
  3. Eur Urol. 2021 Dec 04. pii: S0302-2838(21)02161-8. [Epub ahead of print]
    Renal Neoplasia in Polycystic Kidney Disease: An Assessment of Tuberous Sclerosis Complex-associated Renal Neoplasia and PKD1/TSC2 Contiguous Gene Deletion Syndrome.
    Sounak Gupta, Christine M Lohse, Ross Rowsey, Michael R McCarthy, Wei Shen, Loren Herrera-Hernandez, Stephen A Boorjian, R Houston Thompson, Rafael E Jimenez, Bradley C Leibovich, John C Cheville.
      To determine the incidence of renal neoplasia among patients undergoing nephrectomy for polycystic kidney disease (PKD), we queried our institutional nephrectomy registry (years 2000-2020). Approximately 4% (231 of 5757) of patients who underwent nephrectomy had PKD, and 26 of these 231 patients (11.3%) had renal neoplasia. Tumors from an additional two patients with PKD were also evaluated. Patients with PKD who had tuberous sclerosis complex (TSC)-associated renal neoplasia were screened for PKD1/TSC2 contiguous gene deletion syndrome (CGS) using single nucleotide polymorphism arrays. The median age of patients with PKD and renal neoplasia at nephrectomy was 54 yr. The median tumor size was 2.0 cm and the tumors were predominantly of low grade and stage. The tumors consisted of 23 renal cell carcinomas (RCCs), one epithelioid angiomyolipoma, and four angiomyolipomas. The median follow-up was 59.5 mo (n = 26) and only one patient with clear cell RCC developed metastases. Two patients with angiomyolipomas had PKD1/TSC2 CGS. Our results support screening of patients with PKD and TSC-associated renal neoplasia as well as TSC patients with cystic renal disease for CGS, as identification of patients with CGS can better define the manifestation and prognosis of CGS and guide counseling regarding patterns of inheritance. PATIENT SUMMARY: We identified patients with abnormal kidney cell growth (called renal neoplasia) among those undergoing removal of kidney tissue for polycystic kidney disease (PKD) and patients with a syndrome involving deletions in two genes, called PKD1/TSC2 contiguous gene deletion syndrome (CGS) at our institution. Of 231 PKD patients with removal of kidney tissue, 11.3% had renal neoplasia, and two patients with angiomyolipoma tumors had PKD1/TSC2 CGS. Detection of renal neoplasia associated with a condition called tuberous sclerosis complex in PKD may increase the identification of patients with PKD1/TSC2 CGS and guide patient counseling regarding outcomes and patterns of inheritance.
    Keywords:  PKD1/TSC2 contiguous gene deletion syndrome; Polycystic kidney disease; Tuberous sclerosis complex
    DOI:  https://doi.org/10.1016/j.eururo.2021.11.013
  4. Epilepsy Behav. 2021 Dec 06. pii: S1525-5050(21)00692-2. [Epub ahead of print]126 108431
    Vagus nerve stimulation for drug-resistant epilepsy induced by tuberous sclerosis complex.
    Xuezhi Tong, Xiongfei Wang, Lang Qin, Jian Zhou, Yuguang Guan, Pengfei Teng, Jing Wang, Yujiao Yang, Tianfu Li, Guoming Luan.
      OBJECTIVE: This study investigated the dynamic and long-term efficacy of vagus nerve stimulation (VNS) in patients with drug-resistant epilepsy (DRE) induced by tuberous sclerosis complex (TSC). In addition, the impact of VNS on cognition and emotion after a one-year follow-up was evaluated.METHODS: A total of 17 patients diagnosed with DRE induced by TSC were retrospectively recruited between 2008 and 2019. Dynamic changes in seizure frequency were observed in the responders (≥50% reduction of seizure frequency at last follow-up) and non-responders. Clinical characteristics and seizure outcomes were comprehensively analyzed to determine factors associated with seizure outcomes. The Wechsler intelligence scale was applied in a subgroup of six pediatric patients, whereas the Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) were assessed in a subgroup of nine patients to determine the impact of VNS therapy on cognitive performance and emotional state.
    RESULTS: The follow-up duration for the 17 patients who underwent VNS treatment ranged from 0.5 to 10 years (mean ± SD: 4.1 ± 3.2 years). Monthly seizures decreased significantly from three months to four years post-treatment (p < 0.05). At the last follow-up, 70.6% of the patients achieved at least a 50% reduction in seizure frequency, and three patients were completely seizure free. Comparatively, non-responder patients experienced deterioration of seizure frequency after the first year. Notably, after one-year follow-up the mean standard score of full-scale intelligence quotient increased from 67.33 to 69.5 (p = 0.078) while the mean, standard score of SDS decreased from 49.22 to 45.67 (p = 0.003) compared to preoperative neuropsychological evaluation results.
    CONCLUSION: VNS is a safe and effective treatment for patients with DRE caused by TSC. Although early outcomes were encouraging, a follow-up of at least one-year was required to predict long-term outcomes in patients receiving VNS treatment. Moreover, VNS may improve depressive mood in patients with DRE caused by TSC. Further investigations are needed to validate the present results.
    Keywords:  Depression; Drug-resistant epilepsy; Neuropsychological evaluation; Tuberous sclerosis complex; Vagus nerve stimulation
    DOI:  https://doi.org/10.1016/j.yebeh.2021.108431
  5. Ophthalmic Genet. 2021 Dec 10. 1-3
    Genetics and optical coherence tomography features in a child with an achromatic retinal patch.
    Noy Ashkenazy, Nicolas A Yannuzzi, Audina M Berrocal.
      BACKGROUND: Achromatic retinal patch is associated with tuberous sclerosis. Its role as a diagnostic feature is often overlooked.MATERIALS AND METHODS: A clinical case was retrospectively reviewed and reported.
    RESULTS: A 5-year-old male with a history of seizure disorder and a germline TSC2 variant was found to have a hypopigmented lesion in the nasal macula, most consistent with an achromatic retinal patch. The optical coherence tomography features of the retinal finding is illustrated.
    CONCLUSIONS: We highlight the importance of performing a retinal exam and genetic testing in cases that do not otherwise meet the clinical diagnostic criteria for tuberous sclerosis. The significance of an achromatic retinal patch in the setting of a TSC gene mutation of unclear pathogenic potential remains unknown.
    Keywords:  Tuberous sclerosis; achromatic retinal patch; genetics; optical coherence tomography; pediatric retina
    DOI:  https://doi.org/10.1080/13816810.2021.1989599
  6. Front Genet. 2021 ;12 766354
    A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci.
    Youzhi Li, Xu Zhao, Shanshan Wang, Ke Xu, Xin Zhao, Shanshan Huang, Suiqiang Zhu.
      Familial focal epilepsy with variable foci is an autosomal dominant disorder characterized by partial epilepsy with variable foci. In this study, we report a six-generation with segregation of the mutation present in four generations Chinese family presenting with focal epilepsy with variable foci. Whole exome sequencing confirms a novel pathogenic mutation in the NPRL3 gene (c316C>T; p. Q106*). PCR, Western blotting, and immunohistochemistry were conducted to analyze the gene transcription, protein expression, and subcellular localization of NPRL3 and related signaling molecules in peripheral blood cells from family members. As compared with healthy family members, both mRNA level and protein expression of NPRL3 are decreased in peripheral blood cells of the mutation carrier. In addition, the expression of downstream molecular Phospho-p70 S6 kinase (P-s6k) are increased consequently. Our findings expand the genotypic and phenotypic spectrum of the NPRL3-associated epilepsy and reveal the mechanisms of mTOR pathway signaling and GATOR1 pathogenesis in focal epilepsies, providing exciting potential for future diagnostic and therapeutic interventions. However, further in vitro and animal experiments are still needed to evaluate the role of NPRL3 loss-of-function mutation in epileptogensis.
    Keywords:  GATOR1; Nprl3; familial focal epilepsy with variable foci; mTOR signaling pathway; whole-exome sequencing (WES)
    DOI:  https://doi.org/10.3389/fgene.2021.766354
  7. Autophagy. 2021 Dec 06. 1-3
    An unexpected tumor suppressor role of SQSTM1/p62 in liver tumorigenesis.
    Xiaojuan Chao, Hong-Min Ni, Wen-Xing Ding.
      SQSTM1/p62 (sequestosome 1) is a macroautophagy/autophagy receptor protein that is degraded by selective autophagy. Intracellular accumulation of SQSTM1 activates multiple cell survival signaling pathways including NFΚB/NF-κB (nuclear factor kappa B), MTOR (mechanistic target of rapamycin kinase) and NFE2L2/Nrf2 (nuclear factor, erythroid derived 2, like 2). Both SQSTM1 and NFE2L2 have been considered as oncogenic, and increased accumulation of SQSTM1 and NFE2L2 activation have been frequently observed in various cancers including hepatocellular carcinoma. In a recent study, we found that deletion of Sqstm1 improved hepatic metabolic reprogramming and cell repopulation resulting in the attenuation of liver injury in mice with liver-specific deletion of Atg5 and Tsc1 that have defective hepatic autophagy and persistent MTOR complex 1 (MTORC1) activation. To our surprise, hepatocytic deletion of Sqstm1 promotes liver tumorigenesis in liver-specific atg5 and tsc1 double-knockout mice. Overall, these findings reveal a complex interplay among autophagy, SQSTM1 and MTORC1 and their differential roles either as oncogenic or tumor suppressor in liver tumorigenesis depending on the disease stage and context.
    Keywords:  ATG5; MTOR; Nrf2; Tsc1; autophagy; hepatocellular carcinoma
    DOI:  https://doi.org/10.1080/15548627.2021.2008693
  8. FEBS Open Bio. 2021 Dec 08.
    The mTOR-lysosome axis at the centre of ageing.
    Julian M Carosi, Celia Fourrier, Julien Bensalem, Timothy J Sargeant.
      Age-related diseases represent some of largest unmet clinical needs of our time. While treatment of specific disease-related signs has had some success (for example the effect of statin drugs on slowing progression of atherosclerosis), slowing biological ageing itself represents a target that could significantly increase health-span and reduce the prevalence of multiple age-related diseases. Mechanistic target of rapamycin complex 1 (mTORC1) is known to control fundamental processes in ageing: inhibiting this signalling complex slows biological ageing, reduces age-related disease pathology, and increases lifespan in model organisms. How mTORC1 inhibition achieves this is still subject to ongoing research. However, one mechanism by which mTORC1 inhibition is thought to slow ageing is by activating the autophagy-lysosome pathway. In this review we examine the special bi-directional relationship between mTORC1 and the lysosome. In cells, mTORC1 is located on lysosomes. From this advantageous position, it directly controls the autophagy-lysosome pathway. However, the lysosome also controls mTORC1 activity in numerous ways, creating a special two-way relationship. We then explore specific examples of how inhibition of mTORC1 and activation of the autophagy-lysosome pathway slow the molecular hallmarks of ageing. This body of literature demonstrates that the autophagy-lysosome pathway represents an excellent target for treatments that seek to slow biological ageing and increase health-span in humans.
    Keywords:  Lysosome; age-related disease; aging; autophagy; lysophagy; mTOR
    DOI:  https://doi.org/10.1002/2211-5463.13347
  9. Front Cell Dev Biol. 2021 ;9 775507
    The Cross Talk Between p53 and mTOR Pathways in Response to Physiological and Genotoxic Stresses.
    Danrui Cui, Ruirui Qu, Dian Liu, Xiufang Xiong, Tingbo Liang, Yongchao Zhao.
      The tumor suppressor p53 is activated upon multiple cellular stresses, including DNA damage, oncogene activation, ribosomal stress, and hypoxia, to induce cell cycle arrest, apoptosis, and senescence. Mammalian target of rapamycin (mTOR), an evolutionarily conserved serine/threonine protein kinase, serves as a central regulator of cell growth, proliferation, and survival by coordinating nutrients, energy, growth factors, and oxygen levels. p53 dysfunction and mTOR pathway hyperactivation are hallmarks of human cancer. The balance between response to stresses or commitment to cell proliferation and survival is governed by various regulatory loops between the p53 and mTOR pathways. In this review, we first briefly introduce the tumor suppressor p53 and then describe the upstream regulators and downstream effectors of the mTOR pathway. Next, we discuss the role of p53 in regulating the mTOR pathway through its transcriptional and non-transcriptional effects. We further describe the complicated role of the mTOR pathway in modulating p53 activity. Finally, we discuss the current knowledge and future perspectives on the coordinated regulation of the p53 and mTOR pathways.
    Keywords:  MDM2; mTOR; miRNA; p53; post-translation; transcription; tumorigenesis
    DOI:  https://doi.org/10.3389/fcell.2021.775507
  10. Am J Physiol Endocrinol Metab. 2021 Dec 06.
    Exercise increases phosphorylation of the putative mTORC2 activity readout NDRG1 in human skeletal muscle.
    Jonas Roland Knudsen, Kaspar W Persson, Jaroslawna Meister, Christian Strini Carl, Steffen H Raun, Nicoline R Andersen, Lykke Sylow, Bente Kiens, Thomas E Jensen, Erik A Richter, Maximilian Kleinert.
      In mice, exercise is suggested to activate the mechanistic target of rapamycin complex 2 (mTORC2) in skeletal muscle, and mTORC2 is required for normal muscle glucose uptake during exercise. Whether this translates to human skeletal muscle and what signaling pathways facilitate the exercise-induced mTORC2 activation is unknown but important to determine given the important role of mTORC2 in metabolism. We herein tested the hypothesis that exercise increases mTORC2 activity in human skeletal muscle and investigated if β2-adrenergic receptor (AR) activation mediates exercise-induced mTORC2 activation. We examined several mTORC2 activity readouts (p-NDRG1 Thr346, p-Akt Ser473, p-mTOR S2481, and p-Akt Thr450) in human skeletal muscle biopsies after uphill walking or cycling exercise. In mouse muscles, we assessed mTORC2 activity readouts following acute activation of muscle β2-adrenergic or Gs signaling and during in vivo and ex vivo muscle contractions. Exercise increased phosphorylation of NDRG1 Thr346 in human soleus, gastrocnemius, and vastus lateralis muscle, without changing p-Akt Ser473, p-Akt Thr450, and p-mTOR Ser2481. In mouse muscle, stimulation of β2-adrenergic or Gs signaling and ex vivo contractions failed to increase p-NDRG1 Thr346, while in vivo contractions were sufficient to induce p-NDRG1 Thr346. In conclusion, the mTORC2 activity readout p-NDRG1 Thr346 is a novel exercise-responsive signaling protein in human skeletal muscle. Notably, contraction-induced p-NDRG1 Thr346 appears to require a systemic factor. Unlike exercise, and in contrast to published data obtained in cultured muscles cells, stimulation of β2-adrenergic signaling is not sufficient to trigger NDRG1 phosphorylation in mature mouse skeletal muscle.
    Keywords:  Exercise; Humans; Skeletal muscle; mTORC2; β-adrenergic signaling
    DOI:  https://doi.org/10.1152/ajpendo.00389.2021
  11. Cell Death Dis. 2021 Dec 07. 12(12): 1135
    TTK inhibition increases cisplatin sensitivity in high-grade serous ovarian carcinoma through the mTOR/autophagy pathway.
    Gonghua Qi, Hanlin Ma, Yingwei Li, Jiali Peng, Jingying Chen, Beihua Kong.
      High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy. However, the molecular mechanisms underlying HGSOC development, progression, chemotherapy insensitivity and resistance remain unclear. Two independent GEO datasets, including the gene expression profile of primary ovarian carcinoma and normal controls, were analyzed to identify genes related to HGSOC development and progression. A KEGG pathway analysis of the differentially expressed genes (DEGs) revealed that the cell cycle pathway was the most enriched pathway, among which TTK protein kinase (TTK) was the only gene with a clinical-grade inhibitor that has been investigated in a clinical trial but had not been studied in HGSOC. TTK was also upregulated in cisplatin-resistant ovarian cancer cells from two other datasets. TTK is a regulator of spindle assembly checkpoint signaling, playing an important role in cell cycle control and tumorigenesis in various cancers. However, the function and regulatory mechanism of TTK in HGSOC remain to be determined. In this study, we observed TTK upregulation in patients with HGSOC. High TTK expression was related to a poor prognosis. Genetic and pharmacological inhibition of TTK impeded the proliferation of ovarian cancer cells by disturbing cell cycle progression and increasing apoptosis. TTK silencing increased cisplatin sensitivity by activating the mammalian target of rapamycin (mTOR) complex to further suppress cisplatin-induced autophagy in vitro. In addition, the enhanced sensitivity was partially diminished by rapamycin-mediated inhibition of mTOR in TTK knockdown cells. Furthermore, TTK knockdown increased the toxicity of cisplatin in vivo by decreasing autophagy. These findings suggest that the administration of TTK inhibitors in combination with cisplatin may lead to improved response rates to cisplatin in patients with HGSOC presenting high TTK expression. In summary, our study may provide a theoretical foundation for using the combination therapy of cisplatin and TTK inhibitors as a treatment for HGSOC in the future.
    DOI:  https://doi.org/10.1038/s41419-021-04429-6
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