bims-tubesc 2022-03-13 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2022–03–13
ten papers selected by

The Genetics and Diagnosis of Pediatric Neurocutaneous Disorders: Neurofibromatosis and Tuberous Sclerosis Complex.
Tsc2 knockout counteracts ubiquitin-proteasome system insufficiency and delays photoreceptor loss in retinitis pigmentosa.
Surgery for tuberous sclerosis complex-related epilepsy: Risk factors for an unfavorable seizure outcome.
Multifocal micronodular pneumocyte hyperplasia lacking typical clinical features of the tuberous sclerosis complex: a case report and literature review.
Anaesthetic Management of a Child with West Syndrome Associated with Tuberous Sclerosis Complex at a Remote Location: A Case Report.
Activation of AKT/mammalian target of rapamycin signaling in the peripheral blood of women with premature ovarian insufficiency and its correlation with FMR1 expression.
Dysregulation of mTOR Signaling after Brain Ischemia.
A survey of use of mTOR inhibitors in patients with lymphangioleiomyomatosis listed for lung transplant.
KAT7-mediated CANX (calnexin) crotonylation regulates leucine-stimulated MTORC1 activity.
Mammalian target of rapamycin (mTOR) signaling pathway and traumatic brain injury: A novel insight into targeted therapy.

Clin Dermatol. 2022 Mar 03. pii: S0738-081X(22)00025-6. [Epub ahead of print]

The Genetics and Diagnosis of Pediatric Neurocutaneous Disorders: Neurofibromatosis and Tuberous Sclerosis Complex.

Starling Tolliver, Zoë I Smith, Nanette Silverberg.

  Neurofibromatosis (NF) and tuberous sclerosis complex (TSC) are the two most common neurocutaneous disorders, both transmitted as autosomal dominant or in the case of NF, also as a mosaic conditions. The causative genetic mutations in these neurocutaneous disorders can lead to benign skin changes or uninhibited growth and proliferation in multiple organ systems due to the loss of tumor suppression in MAPK and mTOR signaling pathways. Common clinical features include NF include pigmented lesions, known as café au lait patches, neurofibromas, intertriginous freckles (Crowe's sign), and benign fibrous growths, such as hamartomas in multiple organ systems, and in TS, hypopigmented macules known as ash-leaf spots in addition to neurologic sequelae, such as autism, seizures, and developmental delays. Advances in genetic sequencing technologies have allowed an exponential expansion in the understanding of both NF and TSC. Consensus criteria have been established for both diagnoses that can be confirmed in most cases through gene testing. Once diagnosed, both the clinical and diagnostic value of disease specific surveillance include early identification of benign and malignant tumors. Genetic counseling is important for informed reproductive decision making for both patients and at-risk family members. The improvement in understanding of pathways of pathogenic disease development and oncogenesis in both conditions have produced a new series of therapeutic options that can be used to control seizures and tumor growth. Tremendous advances in life expectancy and quality of life are now a reality due to early introduction of seizure control and novel medications. While we lack cures, early institution of interventions, such as seizure control in tuberous sclerosis, appears to be disease-modifying and holds immense promise to offer patients better lives.

Keywords:  Neurocutaneous disorders; neurofibromatosis; tuberous sclerosis

DOI:  https://doi.org/10.1016/j.clindermatol.2022.02.010
Proc Natl Acad Sci U S A. 2022 Mar 15. 119(11): e2118479119

Tsc2 knockout counteracts ubiquitin-proteasome system insufficiency and delays photoreceptor loss in retinitis pigmentosa.

Yixiao Wang, Claudio Punzo, John D Ash, Ekaterina S Lobanova.

  SignificanceStudies in multiple experimental systems have demonstrated that an increase in proteolytic capacity of post-mitotic cells improves cellular resistance to a variety of stressors, delays cellular aging and senescence. Therefore, approaches to increase the ability of cells to degrade misfolded proteins could potentially be applied to the treatment of a broad spectrum of human disorders. An example would be retinal degenerations, which cause irreversible loss of vision and are linked to impaired protein degradation. This study suggests that chronic activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway in degenerating photoreceptor neurons could stimulate the degradation of ubiquitinated proteins and enhance proteasomal activity through phosphorylation.

Keywords:  mTORC1; photoreceptor; proteasome; protein phosphorylation; retinal degeneration

DOI:  https://doi.org/10.1073/pnas.2118479119
Seizure. 2022 Feb 27. pii: S1059-1311(22)00040-1. [Epub ahead of print]97 8-14

Surgery for tuberous sclerosis complex-related epilepsy: Risk factors for an unfavorable seizure outcome.

Piergiorgio d'Orio, Veronica Pelliccia, Diana Biondi, Pina Scarpa, Francesca Gozzo, Martina Revay, Francesco Cardinale, Laura Tassi, Massimo Cossu.

   PURPOSE: This study aimed to identify risk factors of postoperative seizure outcome in a consecutive cohort of patients operated on for TSC-related focal epilepsy, by evaluating several presurgical and surgical variables, including also MRI-visible brain abnormalities other than cortical tubers.
METHODS: This retrospective study included 51 patients surgically treated for drug-resistant focal epilepsy with a histological diagnosis of cortical tuber and followed for at least 12 months postoperatively. We investigated the association between several potentially explanatory variables and seizure outcome by univariate and multivariate analysis in the whole cohort and in the subgroups of patients with single and multiple tubers, respectively.
RESULTS: The median postoperative follow-up was 115 months (IQR 63-168) and 54.9% of patients were in Engel's class I at final control. In the whole cohort, variables independently associated with an unfavorable seizure outcome (Engel's classes II-IV) were: preoperative non-focal interictal EEG (RR 5, CI 2.46-6.39), presence of sub-ependymal nodules (SEN) (RR 3.53, CI 1.71-4.56) and seizure onset before the first year of age (RR 3.56, CI 0.91-6.89). Non-focal interictal EEG was independently associated with an unfavorable outcome also in the subgroup of patients with multiple tubers (RR 4.34, CI 2.23-5.37), while the presence of SEN (p=0.0221) and of extra-central nervous system lesions (p= 0.0152) predicted an unfavorable seizure outcome in patients with a single tuber.
CONCLUSION: Surgery represents an effective option for seizure control in patients with TSC-related epilepsy. The identification of preoperative risk factors for seizure outcome could be helpful for optimizing patients' selection for surgery and pre-surgical counseling.

Keywords:  Epilepsy surgery; Risk factors; Seizure outcome; Subependymal nodules (SEN); Tuberous sclerosis complex (TSC)

DOI:  https://doi.org/10.1016/j.seizure.2022.02.013
BMC Pulm Med. 2022 Mar 05. 22(1): 77

Multifocal micronodular pneumocyte hyperplasia lacking typical clinical features of the tuberous sclerosis complex: a case report and literature review.

Shan Li, Chaojie Wu, Qiyun Ma, Xueqin Chen, Wei Zhang, Xiao Li, Mao Huang, Ningfei Ji.

   BACKGROUND: Multifocal micronodular pneumocyte hyperplasia (MMPH) is a rare pulmonary manifestation of the tuberous sclerosis complex (TSC) with distinctive histological characteristics. Most case reports of MMPH associated with TSC usually have a history and typical clinical features (seizures, mental retardation, and skin lesions) of TSC. We present a peculiar asymptomatic MMPH case that lacked the history and typical clinical features of TSC.
CASE PRESENTATION: A 56-year-old man was referred to our hospital with bilateral ground-glass opacities (GGOs) on chest computed tomography (CT) lasting 8 months, with no complaint of any discomfort. Because of the lack of clinical manifestations, the diagnosis of MMPH and TSC was confirmed by lung biopsy histopathology and gene sequencing of nonsense mutations in the TSC1 gene. Considering the relevant literature review and that the prognosis of most patients with MMPH is generally stable, no special treatment was given. We followed up with the patient for three years after discharge, and the clinical manifestations and imaging features of the patient were stable.
CONCLUSION: To our best knowledge, this is the first case of MMPH lacking typical clinical manifestations of TSC confirmed by histopathology combined with gene sequencing. MMPH should be considered as one of the differential diagnoses of multiple GGOs in the lung even when the findings of TSC are not recognized.

Keywords:  Case report; Genetic sequencing; Lymphangioleiomyomatosis; Multifocal micronodular pneumocyte hyperplasia; Tuberous sclerosis complex

DOI:  https://doi.org/10.1186/s12890-022-01849-8
Turk J Anaesthesiol Reanim. 2022 Feb;50(1): 72-74

Anaesthetic Management of a Child with West Syndrome Associated with Tuberous Sclerosis Complex at a Remote Location: A Case Report.

Malika Hameed, Muhammad Irfan Ul Haq.

West syndrome is a rare syndrome that consists of a triad of infantile spasms, hypsarrhythmia pattern on electroencephalogram and mental retardation. Tuberous sclerosis complex (TSC) is one of the disorders that can cause it. Radiology suites are considered as remote locations for anaesthesiologists, and the delivery of anaesthesia becomes challenging if a patient with such a rare disease having multiple anaesthetic implications arrives. We present anaesthetic management for the radiological procedure of the MRI brain of a year old paediatric patient with the West syndrome having suspected TSC based on presenting signs and symptoms. Anaesthetic consideration and management of this rare syndrome are discussed. Detailed preoperative assessment, pre-emptive preparation for possible difficult intubation and difficult intravenous access, careful positioning and prevention of seizures should be the goal. Thorough knowledge of the disease process, its manifestation and its management is the key to the successful management of such cases.

DOI: https://doi.org/10.5152/TJAR.2021.1273
Reprod Biol Endocrinol. 2022 Mar 05. 20(1): 44

Activation of AKT/mammalian target of rapamycin signaling in the peripheral blood of women with premature ovarian insufficiency and its correlation with FMR1 expression.

Julia Rehnitz, Birgitta Messmer, Ulrike Bender, Xuan Phuoc Nguyen, Ariane Germeyer, Katrin Hinderhofer, Thomas Strowitzki, Edison Capp.

   BACKGROUND: The protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates early follicular activation and follicular pool maintenance in female germline cells. Fragile X mental retardation 1 (FMR1) regulates folliculogenesis and it is variably expressed in patients with Premature Ovary Insufficiency. FMR1 expression is supposed to be linked to AKT/mTOR signaling in an ovarian response dependent manner as demonstrated in recent in vitro and in vivo studies in the female germline in vitro and in vivo.
METHODS: We evaluated changes in the expression of AKT/mTOR signaling pathway genes by real time PCR in the peripheral blood of 74 patients with Premature Ovarian Insufficiency and 56 fertile controls and correlated their expression with FMR1 expression.
RESULTS: Expression of the genes AKT1, TSC2, mTOR, and S6K was significantly more abundant in patients with POI than in the controls. For AKT1, TSC2 and mTOR, gene expression was not affected by FMR1-CGG repeat number in the 5´-untranslated region. FMR1 and S6K expression levels, however, were significantly upregulated in patients with POI and an FMR1 premutation. Independent of a premutation, expression of mTOR, S6K, and TSC2 was significantly correlated with that of FMR1 in all patients. Furthermore, when grouped according to ovarian reserve, this effect remained significant only for mTOR and S6K, with higher significance note in patients with Premature Ovarian Insufficiency than in the controls.
CONCLUSIONS: In Premature ovarian insufficiency patients, activation of AKT/mTOR signaling pathway is remarkable and putatively pathognomonic. Additionally, it seems to be triggered by an FMR1/mTOR/S6K linkage mechanism, most relevant in premutation carriers.

Keywords:  AKT; Fragile X mental retardation 1 gene; Mammalian target of rapamycin; Premature ovarian insufficiency; S6 kinase; Tuberous sclerosis complex 2

DOI:  https://doi.org/10.1186/s12958-022-00919-0
Int J Mol Sci. 2022 Mar 04. pii: 2814. [Epub ahead of print]23(5):

Dysregulation of mTOR Signaling after Brain Ischemia.

Mario Villa-González, Gerardo Martín-López, María José Pérez-Álvarez.

  In this review, we provide recent data on the role of mTOR kinase in the brain under physiological conditions and after damage, with a particular focus on cerebral ischemia. We cover the upstream and downstream pathways that regulate the activation state of mTOR complexes. Furthermore, we summarize recent advances in our understanding of mTORC1 and mTORC2 status in ischemia-hypoxia at tissue and cellular levels and analyze the existing evidence related to two types of neural cells, namely glia and neurons. Finally, we discuss the potential use of mTORC1 and mTORC2 as therapeutic targets after stroke.

Keywords:  MCAo; astrocytes; brain ischemia; glia; mTOR; mTORC1; mTORC2; microglia; neuron; oligodendrocytes

DOI:  https://doi.org/10.3390/ijms23052814
Respir Med. 2022 Mar 04. pii: S0954-6111(22)00044-0. [Epub ahead of print]195 106779

A survey of use of mTOR inhibitors in patients with lymphangioleiomyomatosis listed for lung transplant.

Krishnan Warrior, Lorriana E Leard, Arun R Nair, Cynthia J Gries, Andrew J Fisher, Simon R Johnson, Francis X McCormack, Daniel F Dilling.

   BACKGROUND: Lymphangioleiomyomatosis (LAM) is an uncommon indication for lung transplantation. The use of mechanistic target of rapamycin (mTOR) inhibitors, which are the mainstay of treatment in progressive LAM, in patients awaiting lung transplant is controversial. We sought to examine worldwide practice patterns in use of mTOR inhibitors in LAM patients on the lung transplant waiting list.
METHODS: We designed and disseminated an online survey about institution-specific practice patterns, particularly regarding listing LAM patients for lung transplant and use of mTOR inhibitors in those patients on the transplant waitlist.
RESULTS: Of the 49 unique respondent programs, 83.6% had previously listed a LAM patient for lung transplant. Thirteen centers allowed patients to continue on mTOR inhibitor until time of lung transplant. None of those centers reported any complications or deaths attributable to mTOR inhibitor adverse effects.
CONCLUSION: There exists significant variability in practice patterns concerning the use of mTOR inhibitors in LAM patients on the lung transplant waiting list. Our survey suggests favorable outcomes for those patients that did continue mTOR inhibitor up to time of transplant. Further data regarding the risk of anastomotic complication with use of mTOR inhibitors in the pre-transplant period would help provide clarity in this debate.

Keywords:  Lung transplant; Lymphangioleiomyomatosis; mTOR inhibitor

DOI:  https://doi.org/10.1016/j.rmed.2022.106779
Autophagy. 2022 Mar 10. 1-18

KAT7-mediated CANX (calnexin) crotonylation regulates leucine-stimulated MTORC1 activity.

Guokai Yan, Xiuzhi Li, Zilong Zheng, Weihua Gao, Changqing Chen, Xinkai Wang, Zhongyi Cheng, Jie Yu, Geng Zou, Muhammad Zahid Farooq, Xiaoyan Zhu, Weiyun Zhu, Qing Zhong, Xianghua Yan.

  Amino acids play crucial roles in the MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) pathway. However, the underlying mechanisms are not fully understood. Here, we establish a cell-free system to mimic the activation of MTORC1, by which we identify CANX (calnexin) as an essential regulator for leucine-stimulated MTORC1 pathway. CANX translocates to lysosomes after leucine deprivation, and its loss of function renders either the MTORC1 activity or the lysosomal translocation of MTOR insensitive to leucine deprivation. We further find that CANX binds to LAMP2 (lysosomal associated membrane protein 2), and LAMP2 is required for leucine deprivation-induced CANX interaction with the Ragulator to inhibit Ragulator activity toward RRAG GTPases. Moreover, leucine deprivation promotes the lysine (K) 525 crotonylation of CANX, which is another essential condition for the lysosomal translocation of CANX. Finally, we find that KAT7 (lysine acetyltransferase 7) mediates the K525 crotonylation of CANX. Loss of KAT7 renders the MTORC1 insensitivity to leucine deprivation. Our findings provide new insights for the regulatory mechanism of the leucine-stimulated MTORC1 pathway.

Keywords:  CANX; KAT7; LAMP2; MTORC1; leucine; lysine crotonylation; ragulator

DOI:  https://doi.org/10.1080/15548627.2022.2047481
Cell Biochem Funct. 2022 Mar 08.

Mammalian target of rapamycin (mTOR) signaling pathway and traumatic brain injury: A novel insight into targeted therapy.

Ahmad Movahedpour, Omid Vakili, Masoomeh Khalifeh, Pegah Mousavi, Amir Mahmoodzadeh, Mortaza Taheri-Anganeh, Saeed Razmeh, Zahra Shabaninejad, Fatemeh Yousefi, Hamid Behrouj, Hassan Ghasemi, Seyyed Hossein Khatami.

  Traumatic brain injury (TBI) is one of the most concerning health issues in which the normal brain function may be disrupted as a result of a blow, bump, or jolt to the head. Loss of consciousness, amnesia, focal neurological defects, alteration in mental state, and destructive diseases of the nervous system such as cognitive impairment, Parkinson's, and Alzheimer's disease. Parkinson's disease is a chronic progressive neurodegenerative disorder, characterized by the early loss of striatal dopaminergic neurons. TBI is a major risk factor for Parkinson's disease. Existing therapeutic approaches have not been often effective, indicating the necessity of discovering more efficient therapeutic targets. The mammalian target of rapamycin (mTOR) signaling pathway responds to different environmental cues to modulate a large number of cellular processes such as cell proliferation, survival, protein synthesis, autophagy, and cell metabolism. Moreover, mTOR has been reported to affect the regeneration of the injured nerves throughout the central nervous system (CNS). In this context, recent evaluations have revealed that mTOR inhibitors could be potential targets to defeat a group of neurological disorders, and thus, a number of clinical trials are investigating their efficacy in treating dementia, autism, epilepsy, stroke, and brain injury, as irritating neurological defects. The current review describes the interplay between mTOR signaling and major CNS-related disorders (esp. neurodegenerative diseases), as well as the mTOR signaling-TBI relationship. It also aims to discuss the promising therapeutic capacities of mTOR inhibitors during the TBI.

Keywords:  TOR serine-threonine kinases; brain injuries; central nervous system; mTOR inhibitors; neurodegenerative diseases

DOI:  https://doi.org/10.1002/cbf.3692