bims-tubesc 2022-08-14 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2022–08–14
twelve papers selected by

Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex.
Epilepsy and Language Development in 8-36-Month-Old Toddlers with Tuberous Sclerosis Complex.
Loss of Heterozygosity for Tuberous Sclerosis Complex and Mammalian Target of Rapamycin Signaling: The Keys to Understanding the Pathogenesis of Diffuse Cystic Lung Diseases?
Dissecting the roles of the Tuberin protein in the subcellular localization of the G2/M Cyclin, Cyclin B1.
Generation of TSC1 knockout induced pluripotent stem cell (iPSC) line.
[Tuberous sclerosis complex].
mTOR Complex 1 Content and Regulation Is Adapted to Animal Longevity.
Neuromyelitis Optica in a Young Woman With Tuberous Sclerosis: Is There an Association?
mTORC1 controls Golgi architecture and vesicle secretion by phosphorylation of SCYL1.
Abdominal aortic aneurysm in a child with tuberous sclerosis.
Oncolytic Avian Reovirus p17-Modulated Inhibition of mTORC1 by Enhancement of Endogenous mTORC1 Inhibitors Binding to mTORC1 To Disrupt Its Assembly and Accumulation on Lysosomes.
PEBP4 Directs the Malignant Behavior of Hepatocellular Carcinoma Cells via Regulating mTORC1 and mTORC2.

Nat Commun. 2022 Aug 09. 13(1): 4665

Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex.

Vasiliki Karalis, Franklin Caval-Holme, Helen S Bateup.

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that negatively regulate mTOR complex 1 (mTORC1) signaling. Current treatment strategies focus on mTOR inhibition with rapamycin and its derivatives. While effective at improving some aspects of TSC, chronic rapamycin inhibits both mTORC1 and mTORC2 and is associated with systemic side-effects. It is currently unknown which mTOR complex is most relevant for TSC-related brain phenotypes. Here we used genetic strategies to selectively reduce neuronal mTORC1 or mTORC2 activity in mouse models of TSC. We find that reduction of the mTORC1 component Raptor, but not the mTORC2 component Rictor, rebalanced mTOR signaling in Tsc1 knock-out neurons. Raptor reduction was sufficient to improve several TSC-related phenotypes including neuronal hypertrophy, macrocephaly, impaired myelination, network hyperactivity, and premature mortality. Raptor downregulation represents a promising potential therapeutic intervention for the neurological manifestations of TSC.

DOI: https://doi.org/10.1038/s41467-022-31961-6
J Clin Med. 2022 Aug 04. pii: 4564. [Epub ahead of print]11(15):

Epilepsy and Language Development in 8-36-Month-Old Toddlers with Tuberous Sclerosis Complex.

Małgorzata Foryś-Basiejko, Katarzyna Kotulska, Agnieszka Maryniak, Agata Siłuszyk, Monika Szkop, Julita Borkowska, Monika Sugalska, Jagoda Głowacka-Walas, Sergiusz Jóźwiak.

  This paper aimed to assess language development in infants and toddlers with tuberous sclerosis complex (TSC) and epilepsy, which increase the risk of autism spectrum disorder. We assessed language development in 61 patients with TSC at 8-36 months using a standardized Speech Development and Communication Inventory tool. The results showed differences in outcomes due to the duration of the seizures and the number of drugs (pFDR = 0.007 **-pFDR = 0.037 *). Children with TSC with longer epilepsy duration and receiving more antiepileptic drugs have a greater risk of language development delay.

Keywords:  epilepsy; gesture production; language development; tuberous sclerosis complex; vocabulary

DOI:  https://doi.org/10.3390/jcm11154564
Chest. 2022 Aug;pii: S0012-3692(22)00449-4. [Epub ahead of print]162(2): 279-280

Loss of Heterozygosity for Tuberous Sclerosis Complex and Mammalian Target of Rapamycin Signaling: The Keys to Understanding the Pathogenesis of Diffuse Cystic Lung Diseases?

Marissa O'Callaghan, Cormac McCarthy.

DOI: https://doi.org/10.1016/j.chest.2022.03.016
PLoS One. 2022 ;17(8): e0272741

Dissecting the roles of the Tuberin protein in the subcellular localization of the G2/M Cyclin, Cyclin B1.

Adam Pillon, Jessica Dare-Shih, Jackie Fong, Elizabeth Fidalgo da Silva, Lisa A Porter.

Tuberin is a major component of the protein regulatory complex known as the Tuberous Sclerosis Complex and plays a crucial role in cell cycle progression and protein synthesis. Mutations in the Tuberin gene, TSC2, lead to the formation of benign tumors in many organ systems and causes the Tuberous Sclerosis Complex disorder. Genotypes ranging from point mutations to large deletions in the TSC2 gene have been clinically characterized with a wide range of phenotypes from skin tumors to large brain tumors. Our lab has previously demonstrated that Tuberin can directly bind and regulate the timing of nuclear transport of the G2/M cyclin, Cyclin B1. Herein we study the consequence of one clinically relevant truncation in the Tuberin protein on cell cycle function. We demonstrate that exogenous expression of a fragment of the N-term region of Tuberin alters the subcellular localization of Cyclin B1 and increases cell proliferation. This adds to our body of information about the residues within Tuberin responsible for regulating the cytoplasmic retention of Cyclin B1 and supports the phenotypic data seen in the clinic with Tuberous Sclerosis Complex patients harbouring similar large deletions in Tuberin.

DOI: https://doi.org/10.1371/journal.pone.0272741
Stem Cell Res. 2022 Aug 05. pii: S1873-5061(22)00237-9. [Epub ahead of print]64 102888

Generation of TSC1 knockout induced pluripotent stem cell (iPSC) line.

Wei Shan, Huajun Yang, Qian Ren, Qun Wang, Guipeng An.

The TSC1 gene is a tumor suppressor gene that encodes for the growth inhibitory protein hamartin. It was founded clinically relevant to tuberous sclerosis complex (TSC) and related epilepsy. Variants in TSC1 resulted in tuberous sclerosis, focal cortical dysplasia (FCD) Type II, pulmonary lymphangioleiomyomatosis and change in everolimus sensitivity. Here, we generated induced pluripotent stem cells (iPSC) from a normal individual by electroporation of peripheral blood mononuclear cells (PBMC), and further generated TSC1-knockout human iPSC line via CRISPR/Cas9 gene editing. The resulting iPSCs had normal karyotype, free of genomically integrated epitomal plasmids, expressed pluripotency markers, and maintained trilineage differentiation potential.

DOI: https://doi.org/10.1016/j.scr.2022.102888
Radiologie (Heidelb). 2022 Aug 09.

[Tuberous sclerosis complex].

Katja Glutig, Ralf Husain, Diane Renz, Ulrike John-Kroegel, Hans-Joachim Mentzel.

   CLINICAL BACKGROUND: Tuberous sclerosis complex (TSC) is a phakomatosis and is a tumor predisposition syndrome. As a genetic multisystem disease, patients present with a broad range of changes in the brain, heart, skin, kidneys, and lungs.
OBJECTIVES: Which imaging modalities are required to monitor TSC patients according to current international recommendations?
MATERIALS AND METHODS: Common findings in TSC are cortical tubers, subependymal nodules, and giant cell astrocytomas in the central nervous system (CNS), rhabdomyomas in the heart, and cysts and angiomyolipomas in the kidneys. Magnetic resonance imaging (MRI) of the brain and kidneys and abdominal ultrasound are the imaging modalities of choice, due to the very good soft tissue contrast and lack of X‑ray radiation.
RESULTS: Using standard and functional MRI sequences in a multimodal approach, the type, malignancy, size, and morphology of changes in TSC can be reliably determined. Abdominal ultrasound using high-resolution transducers can be used to rapidly and reliably detect even the smallest changes in the kidneys.
CONCLUSION: Regular follow-up of patients with TSC using MRI and ultrasound is necessary for early detection of complications, for planning individualized therapy, and for optimal lifelong care.

Keywords:  Angiomyolipoma; Epilepsy; Phacomatosis; Rhabdomyoma; Tumor predisposition syndrome

DOI:  https://doi.org/10.1007/s00117-022-01053-z
Int J Mol Sci. 2022 Aug 06. pii: 8747. [Epub ahead of print]23(15):

mTOR Complex 1 Content and Regulation Is Adapted to Animal Longevity.

Natalia Mota-Martorell, Mariona Jové, Reinald Pamplona.

  Decreased content and activity of the mechanistic target of rapamycin (mTOR) signalling pathway, as well as the mTOR complex 1 (mTORC1) itself, are key traits for animal species and human longevity. Since mTORC1 acts as a master regulator of intracellular metabolism, it is responsible, at least in part, for the longevous phenotype. Conversely, increased content and activity of mTOR signalling and mTORC1 are hallmarks of ageing. Additionally, constitutive and aberrant activity of mTORC1 is also found in age-related diseases such as Alzheimer's disease (AD) and cancer. The downstream processes regulated through this network are diverse, and depend upon nutrient availability. Hence, multiple nutritional strategies capable of regulating mTORC1 activity and, consequently, delaying the ageing process and the development of age-related diseases, are under continuous study. Among these, the restriction of calories is still the most studied and robust intervention capable of downregulating mTOR signalling and feasible for application in the human population.

Keywords:  age-related diseases; ageing; longevity; mTORC1; metabolism

DOI:  https://doi.org/10.3390/ijms23158747
J Investig Med High Impact Case Rep. 2022 Jan-Dec;10:10 23247096221117808

Neuromyelitis Optica in a Young Woman With Tuberous Sclerosis: Is There an Association?

Mahmoud Elkhooly, Rube Jacob, Samiksha Sirvastava, Shitz Sirwastava, Robert Lisak, Evanthia Bernitsas.

  Tuberous sclerosis complex (TSC) is a genetic neurocutaneous disorder that presents with multi-organ involvement, including but not limited to hamartomas in the brain, eyes, heart, lung, liver, kidney, and skin. Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory, autoimmune, demyelinating, central nervous system disorder, targeting the optic nerves and spinal cord. We report a 30-year-old woman with TSC who developed tingling in the legs that gradually involved her abdomen. Additional symptoms included severe vomiting that lasted for a week and spasms in her legs. One month later, she was hospitalized due to difficulty ambulating and tingling in her hands. Magnetic resonance imaging (MRI) of her spine showed longitudinally extensive upper cervical and lower thoracic cord signal changes. MRI scan of her brain showed few non-specific T2 signal changes along with cortical and subcortical tubers. Aquaporin (AQP4) IgG antibody was found to be positive in both serum and cerebrospinal fluid. Accordingly, she was diagnosed with NMOSD, treated with a 5-day course of intravenous steroids, followed by 5 sessions of plasma exchange. After her initial improvement, she was started on rituximab as maintenance therapy. Two years later, she is clinically stable, and her follow-up MRI showed marked improvement.

Keywords:  aquaporin-4 antibody; neuromyelitis optica; tuberous sclerosis complex

DOI:  https://doi.org/10.1177/23247096221117808
Nat Commun. 2022 Aug 10. 13(1): 4685

mTORC1 controls Golgi architecture and vesicle secretion by phosphorylation of SCYL1.

Stéphanie Kaeser-Pebernard, Christine Vionnet, Muriel Mari, Devanarayanan Siva Sankar, Zehan Hu, Carole Roubaty, Esther Martínez-Martínez, Huiyuan Zhao, Miguel Spuch-Calvar, Alke Petri-Fink, Gregor Rainer, Florian Steinberg, Fulvio Reggiori, Jörn Dengjel.

The protein kinase mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and proliferation, supporting anabolic reactions and inhibiting catabolic pathways like autophagy. Its hyperactivation is a frequent event in cancer promoting tumor cell proliferation. Several intracellular membrane-associated mTORC1 pools have been identified, linking its function to distinct subcellular localizations. Here, we characterize the N-terminal kinase-like protein SCYL1 as a Golgi-localized target through which mTORC1 controls organelle distribution and extracellular vesicle secretion in breast cancer cells. Under growth conditions, SCYL1 is phosphorylated by mTORC1 on Ser754, supporting Golgi localization. Upon mTORC1 inhibition, Ser754 dephosphorylation leads to SCYL1 displacement to endosomes. Peripheral, dephosphorylated SCYL1 causes Golgi enlargement, redistribution of early and late endosomes and increased extracellular vesicle release. Thus, the mTORC1-controlled phosphorylation status of SCYL1 is an important determinant regulating subcellular distribution and function of endolysosomal compartments. It may also explain the pathophysiology underlying human genetic diseases such as CALFAN syndrome, which is caused by loss-of-function of SCYL1.

DOI: https://doi.org/10.1038/s41467-022-32487-7
J Vasc Surg Cases Innov Tech. 2022 Sep;8(3): 375-377

Abdominal aortic aneurysm in a child with tuberous sclerosis.

Sabrina Lasini Gruhl, Yi Chuan Tham, York Tien Lee, Masakazu Nakao.

  Abdominal aortic aneurysm is rare in the pediatric population and even more uncommon in association with tuberous sclerosis. We have presented a unique case of a 3-year, 8-month-old girl who was successfully treated. She was admitted because of breakthrough seizures. A painless pulsatile abdominal mass on examination prompted an abdominal ultrasound scan, which identified a large saccular abdominal aortic aneurysm. Urgent replacement of the abdominal aorta with a 12-mm woven Dacron graft was undertaken. A postoperative ultrasound evaluation confirmed the successful repair. She was growing well when examined 7 months after surgery.

Keywords:  Abdominal aortic aneurysm; Pediatric aneurysms; Tuberous sclerosis

DOI:  https://doi.org/10.1016/j.jvscit.2022.05.018
J Virol. 2022 Aug 10. e0083622

Oncolytic Avian Reovirus p17-Modulated Inhibition of mTORC1 by Enhancement of Endogenous mTORC1 Inhibitors Binding to mTORC1 To Disrupt Its Assembly and Accumulation on Lysosomes.

Jyun-Yi Li, Wei-Ru Huang, Tsai-Ling Liao, Brent L Nielsen, Hung-Jen Liu.

  The mechanism by which avian reovirus (ARV)-modulated suppression of mTORC1 triggers autophagy remains largely unknown. In this work, we determined that p17 functions as a negative regulator of mTORC1. This study suggest novel mechanisms whereby p17-modulated inhibition of mTORC1 occurs via upregulation of p53, inactivation of Akt, and enhancement of binding of the endogenous mTORC1 inhibitors (PRAS40, FKBP38, and FKPP12) to mTORC1 to disrupt its assembly and accumulation on lysosomes. p17-modulated inhibition of Akt leads to activation of the downstream targets PRAS40 and TSC2, which results in mTORC1 inhibition, thereby triggering autophagy and translation shutoff, which is favorable for virus replication. p17 impairs the interaction of mTORC1 with its activator Rheb, which promotes FKBP38 interaction with mTORC1. It is worth noting that p17 activates ULK1 and Beclin1 and increases the formation of the Beclin 1/class III PI3K complex. These effects could be reversed in the presence of insulin or depletion of p53. Furthermore, we found that p17 induces autophagy in cancer cell lines by upregulating the p53/PTEN pathway, which inactivates Akt and mTORC1. This study highlights p17-modulated inhibition of Akt and mTORC1, which triggers autophagy and translation shutoff by positively modulating the tumor suppressors p53 and TSC2 and endogenous mTORC1 inhibitors. IMPORTANCE The mechanisms by which p17-modulated inhibition of mTORC1 induces autophagy and translation shutoff is elucidated. In this work, we determined that p17 serves as a negative regulator of mTORC1. This study provides several lines of conclusive evidence demonstrating that p17-modulated inhibition of mTORC1 occurs via upregulation of the p53/PTEN pathway, downregulation of the Akt/Rheb/mTORC1 pathway, enhancement of binding of the endogenous mTORC1 inhibitors to mTORC1 to disrupt its assembly, and suppression of mTORC1 accumulation on lysosomes. This work provides valuable information for better insights into p17-modulated inhibition of mTORC1, which induces autophagy and translation shutoff to benefit virus replication.

Keywords:  Akt; PRAS40; Rheb; TSC2; autophagy; avian reovirus; mTORC1; p17; p53; translation shutoff

DOI:  https://doi.org/10.1128/jvi.00836-22
Int J Mol Sci. 2022 Aug 08. pii: 8798. [Epub ahead of print]23(15):

PEBP4 Directs the Malignant Behavior of Hepatocellular Carcinoma Cells via Regulating mTORC1 and mTORC2.

Qiongfeng Chen, Jingguang Jin, Wenhui Guo, Zhimin Tang, Yunfei Luo, Ying Ying, Hui Lin, Zhijun Luo.

  Phosphatidylethanolamine binding protein 4 (PEBP4) is an understudied multifunctional small protein. Previous studies have shown that the expression of PEBP4 is increased in many cancer specimens, which correlates to cancer progression. The present study explored the mechanism by which PEBP4 regulates the growth and progression of hepatocellular carcinoma cells. Thus, we showed that knockdown of PEBP4 in MHCC97H cells, where its expression was relatively high, diminished activities of serine/threonine protein kinase B (PKB, also known as Akt), mammalian target of rapamycin complex 1(mTORC1), and mTORC2, events that were not restored by insulin-like growth factor 1 (IGF-1). Conversely, overexpression of PEBP4 in MHCC97L cells with the low endogenous level yielded opposite effects. Furthermore, physical association of PEBP4 with Akt, mTORC1, and mTORC2 was observed. Interestingly, introduction of AktS473D mutant, bypassing phosphorylation by mTORC2, rescued mTORC1 activity, but without effects on mTORC2 signaling. In contrast, the effect of PEBP4 overexpression on the activity of mTORC1 but not that of mTORC2 was suppressed by MK2206, a specific inhibitor of Akt. In conjunction, PEBP4 knockdown-engendered reduction of cell proliferation, migration and invasion was partially rescued by Akt S473D while increases in these parameters induced by overexpression of PEBP4 were completely abolished by MK2206, although the expression of epithelial mesenchymal transition (EMT) markers appeared to be fully regulated by the active mutant of Akt. Finally, knockdown of PEBP4 diminished the growth of tumor and metastasis, whereas they were enhanced by overexpression of PEBP4. Altogether, our study suggests that increased expression of PEBP4 exacerbates malignant behaviors of hepatocellular cancer cells through cooperative participation of mTORC1 and mTORC2.

Keywords:  Akt; HCC; PEBP4; mTORC1; mTORC2

DOI:  https://doi.org/10.3390/ijms23158798