bims-tubesc 2022-09-04 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2022‒09‒04
eleven papers selected by
Marti Cadena Sandoval
Columbia University

Therapeutic effect of everolimus on small renal angiomyolipoma in cases of tuberous sclerosis complex-related epilepsy and subependymal giant cell astrocytoma.
DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting.
Tuberous sclerosis complex with skin lesions as the initial presentation: A case report and multidisciplinary discussion.
White matter disruptions related to inattention and autism spectrum symptoms in tuberous sclerosis complex.
Mosaicism in Tuberous Sclerosis Complex - Lowering the Threshold for Clinical Reporting.
[Tuberous sclerosis complex: diagnosis and current treatment].
Pediatric chordoma associated with tuberous sclerosis complex: A rare case report with a thorough analysis of potential therapeutic molecular targets.
Association of multiple retinal nodular hamartomas and "confetti" skin lesions with end-stage renal disease in patients with tuberous sclerosis.
GluN2C selective inhibition is a target to develop new antiepileptic compounds.
The trilateral interactions between mammalian target of rapamycin (mTOR) signaling, the circadian clock, and psychiatric disorders: an emerging model.
The RNA-binding protein AUF1 facilitates Akt phosphorylation at the membrane.

Asian J Surg. 2022 Aug 25. pii: S1015-9584(22)01155-1. [Epub ahead of print]

Therapeutic effect of everolimus on small renal angiomyolipoma in cases of tuberous sclerosis complex-related epilepsy and subependymal giant cell astrocytoma.

Takashi Hatano, Yasuhiro Yuri.



Keywords:  Epilepsy; Everolimus; Mammalian target of rapamycin inhibitor; Renal angiomyolipoma; Subependymal giant cell astrocytoma; Tuberous sclerosis complex

DOI:  https://doi.org/10.1016/j.asjsur.2022.08.041
Cell Rep. 2022 Aug 30. pii: S2211-1247(22)01098-1. [Epub ahead of print]40(9): 111278

DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting.

Christopher J Yuskaitis, Jinita B Modasia, Sandra Schrötter, Leigh-Ana Rossitto, Karenna J Groff, Christopher Morici, Divakar S Mithal, Ram P Chakrabarty, Navdeep S Chandel, Brendan D Manning, Mustafa Sahin.

  Caloric restriction and acute fasting are known to reduce seizures but through unclear mechanisms. mTOR signaling has been suggested as a potential mechanism for seizure protection from fasting. We demonstrate that brain mTORC1 signaling is reduced after acute fasting of mice and that neuronal mTORC1 integrates GATOR1 complex-mediated amino acid and tuberous sclerosis complex (TSC)-mediated growth factor signaling. Neuronal mTORC1 is most sensitive to withdrawal of leucine, arginine, and glutamine, which are dependent on DEPDC5, a component of the GATOR1 complex. Metabolomic analysis reveals that Depdc5 neuronal-specific knockout mice are resistant to sensing significant fluctuations in brain amino acid levels after fasting. Depdc5 neuronal-specific knockout mice are resistant to the protective effects of fasting on seizures or seizure-induced death. These results establish that acute fasting reduces seizure susceptibility in a DEPDC5-dependent manner. Modulation of nutrients upstream of GATOR1 and mTORC1 could offer a rational therapeutic strategy for epilepsy treatment.

Keywords:  CP: Metabolism; CP: Neuroscience; GATOR1; SUDEP; TSC; amino acids; cell signaling; epilepsy; fasting; mTOR; metabolomics; seizures

DOI:  https://doi.org/10.1016/j.celrep.2022.111278
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2022 Jul 28. pii: 1672-7347(2022)07-0973-08. [Epub ahead of print]47(7): 973-980

Tuberous sclerosis complex with skin lesions as the initial presentation: A case report and multidisciplinary discussion.

Sihan Deng, Wei Shi, Yi Cai, Yongjun Tang, Weiping Liu, Ping Yin, Chen Chen, Li Meng, Huixi Dong, Jundong Huang, Yu Liu.

  We reported a case of tuberous sclerosis complex with facial angiofibroma as the initial presentation and conducted a multidisciplinary discussion. The patient, a young female, was admitted to the Department of Dermatology for cosmetic purpose. After the examination, she was found to have multiple system involvement, including a large renal angiomyolipoma pressing on the liver. She never had any subjective symptom. After consultation by the multidisciplinary team of tuberous sclerosis complex, the patient was treated with everolimus orally and followed up regularly. It is suggested that dermatologists should pay attention to the systemic involvement of patients with tuberous sclerosis complex. Early intervention can prolong the life of patients and improve their life quality. Multidisciplinary collaboration for lifelong disease management is the key to enhance the diagnosis and treatment for tuberous sclerosis complex and enhance the prognosis of patients.

Keywords:  angiofibroma; angiomyolipoma; multidisciplinary team; tuberous sclerosis complex

DOI:  https://doi.org/10.11817/j.issn.1672-7347.2022.210452
Neuroimage Clin. 2022 Aug 25. pii: S2213-1582(22)00228-5. [Epub ahead of print]36 103163

White matter disruptions related to inattention and autism spectrum symptoms in tuberous sclerosis complex.

TS2000 Study Team

  Tuberous sclerosis complex is a rare genetic multisystem condition that is associated with a high prevalence of neurodevelopmental disorders such as autism and attention-deficit/hyperactivity disorder. The underlying neural mechanisms of the emergence of these symptom domains in tuberous sclerosis complex remain unclear. Here, we use fixel-based analysis of diffusion-weighted imaging, which allows for the differentiation between multiple fibre populations within a voxel, to compare white matter properties in 16 participants with tuberous sclerosis complex (aged 11-19) and 12 age and sex matched control participants. We further tested associations between white matter alterations and autism and inattention symptoms as well as cognitive ability in participants with tuberous sclerosis complex. Compared to controls, participants with tuberous sclerosis complex showed reduced fibre density cross-section (FDC) in the dorsal branch of right superior longitudinal fasciculus and bilateral inferior longitudinal fasciculus, reduced fibre density (FD) in bilateral tapetum, and reduced fibre cross-section (FC) in the ventral branch of right superior longitudinal fasciculus. In participants with tuberous sclerosis complex, the extent of FDC reductions in right superior longitudinal fasciculus was significantly associated with autism traits (social communication difficulties and restricted, repetitive behaviours), whereas FDC reductions in right inferior longitudinal fasciculus were associated with inattention. The observed white matter alterations were unrelated to cognitive ability. Our findings shed light on the fibre-specific biophysical properties of white matter alterations in tuberous sclerosis complex and suggest that these regional changes are selectively associated with the severity of neurodevelopmental symptoms.

Keywords:  Autism; Fixel-based analysis; Inattention; Neurodevelopment; Tuberous sclerosis complex; White matter

DOI:  https://doi.org/10.1016/j.nicl.2022.103163
Hum Mutat. 2022 Aug 28.

Mosaicism in Tuberous Sclerosis Complex - Lowering the Threshold for Clinical Reporting.

Zimeng Ye, Sufang Lin, Xia Zhao, Mark F Bennet, Natasha J Brown, Mathew Wallis, Xinyi Gao, Li Sun, Jiarui Wu, Ravikiran Vedururu, Tom Witkowski, Fiona Gardiner, Chloe Stutterd, Jing Duan, Saul A Mullen, George McGillivray, Simon Bodek, Giulia Valente, Matthew Reagan, Yi Yao, Lin Li, Li Chen, Amber Boys, Thiuni N Adikari, Dezhi Cao, Zhanqi Hu, Victoria Beshay, Victor W Zhang, Samuel F Berkovic, Ingrid E Scheffer, Jianxiang Liao, Michael S Hildebrand.

  Tuberous sclerosis complex (TSC) is a multi-system genetic disorder. Most patients have germline mutations in TSC1 or TSC2 but, 10-15% patients do not have TSC1/TSC2 mutations detected on routine clinical genetic testing. We investigated the contribution of low-level mosaic TSC1/TSC2 mutations in unsolved sporadic patients and families with TSC. Thirty-one sporadic TSC patients negative on routine testing and 8 families with suspected parental mosaicism were sequenced using deep panel sequencing followed by droplet digital PCR. Pathogenic variants were found in 22/31 (71%) unsolved sporadic patients, 16 were mosaic (median variant allele fraction (VAF) 6.8% in blood) and 6 had missed germline mutations. Parental mosaicism was detected in 5/8 families (median VAF 1% in blood). Clinical testing laboratories typically only report pathogenic variants with allele fractions above 10%. Our findings highlight the critical need to change laboratory practice by implementing higher sensitivity assays to improve diagnostic yield, inform patient management and guide reproductive counseling. (154/200 words) This article is protected by copyright. All rights reserved.

Keywords:  Tuberous sclerosis complex; high-depth sequencing; mosaic mutations; parental mosaicism

DOI:  https://doi.org/10.1002/humu.24454
Medicina (B Aires). 2022 Aug 30. 82 Suppl 3 71-75

[Tuberous sclerosis complex: diagnosis and current treatment].

Alfredo Cerisola, Lucía Cibils, María Eugenia Chaibún, Virginia Pedemonte, Melania Rosas.

Tuberous sclerosis complex is an autosomal dominant genetic multisystemic disorder caused primarily by mutations in one of the two tumor suppressor genes TSC1 or TSC2, resulting in increased activation of the mTOR pathway. Regarding clinical manifestations, a wide range of phenotypic variability exists, with symptoms constellations that may differ in affected organs (brain, skin, heart, eyes, kidneys, lungs), age of presentation and severity, but usually with great impact in biopsychosocial aspects of health and in quality of life. Main clinical neurological features are epilepsy (frequently, antiepileptic drug-resistant epilepsy), neuropsychiatric disorders, and subependymal giant cell astrocytomas. Recently, many therapeutic strategies have developed, including preventive treatment of epilepsy, new options for treatment of epilepsy as cannabidiol, mTOR inhibitors, ketogenic diet, and a more precise epilepsy surgery. Subependymal giant cell astrocytomas may require surgical procedures or mTOR inhibitors treatment. mTOR inhibitors may also be useful for other comorbidities. To improve quality of life of patients with tuberous sclerosis complex, it is essential to be able to deliver an integrated approach by specialized multidisciplinary teams, coordinated with primary care physicians and health professionals, that include access to treatments, attention of psychosocial aspects, and an adequate health care transition from pediatric to adult care.

Keywords: cannabidiol; epilepsy; ketogenic diet; mTOR inhibitors; subependymal giant cell astrocytoma; tuberous sclerosis
Heliyon. 2022 Aug;8(8): e10291

Pediatric chordoma associated with tuberous sclerosis complex: A rare case report with a thorough analysis of potential therapeutic molecular targets.

Kirill Anoshkin, Denis Zosen, Kristina Karandasheva, Maxim Untesco, Ilya Volodin, Ekaterina Alekseeva, Anna Parfenenkova, Eugenia Snegova, Aleksandr Kim, Marina Dorofeeva, Sergei Kutsev, Vladimir Strelnikov.

  Chordoma associated with tuberous sclerosis complex (TSC) is an extremely rare tumor that was described only in 13 cases since 1975. Сhordoma itself is a malignant slow-growing bone tumor thought to arise from vestigial or ectopic notochordal tissue. Chordoma associated with TSC differs from chordoma in the general pediatric population in the median age, where the diagnosis of TSC-associated chordoma is 6.2 months, whereas for chordoma in the general pediatric population it is set to 12 years. The majority of TSC-associated chordomas are localized in skull-based and sacrum regions, and rare in the spine. Chordomas are genetically heterogeneous tumors characterized by chromosomal instability (CIN), and alterations involving PI3K-AKT signaling pathway genes and chromatin remodeling genes. Here we present the 14th case of chordoma associated with TSC in a 1-year-old pediatric patient. Alongside biallelic inactivation of the TSC1 gene, molecular genetic analysis revealed CIN and involvement of epigenetic regulation genes. In addition, we found the engagement of CBX7 and apolipoprotein B editing complex (APOBEC3) genes that were not yet seen in chordomas before. Amplification of CBX7 may epigenetically silence the CDKN2A gene, whereas amplification of APOBEC3 genes can explain the frequent occurrence of CIN in chordomas. We also found that KRAS gene is located in the region with gain status, which may suggest the ineffectiveness of potential EGFR monotherapy. Thus, molecular genetic analysis carried out in this study broadens the horizons of possible approaches for targeted therapies with potential applications for personalized medicine.

Keywords:  APOBEC3; CBX7; CMA; Chordoma; HTS; NGS; TSC

DOI:  https://doi.org/10.1016/j.heliyon.2022.e10291
Int Urol Nephrol. 2022 Aug 28.

Association of multiple retinal nodular hamartomas and "confetti" skin lesions with end-stage renal disease in patients with tuberous sclerosis.

Vladimir Prelevic, Ivana Juric, Sebastijan Bevc, Natasa Marcun-Varda, Mirna Aleckovic-Halilovic, Enisa Mesic, Hrvoje Bilic, Milorad Grujicic, Igor Zabic, Josipa Josipovic, Bozidar Vujicic, Smaragdi Marinaki, Sanja Simic-Ogrizovic, Marija Milinkovic, Tijana Azasevac, Alma Idrizi, Miha Arnol, Danilo Radunovic, Tanja Antunovic, Nikolina Basic- Jukic.

  PURPOSE: The main purpose of this study is to explore characteristics of patients with chronic kidney disease in tuberous sclerosis (TSC) and to underline differences in clinical characteristics between end-stage renal disease (ESRD) patients and patients in earlier stages of chronic kidney disease.METHODS: This multicentric, retrospective study included data for 48 patients from seven South-Eastern European countries (Albania, Bosnia and Herzegovina, Croatia, Greece, Montenegro, Serbia, Slovenia) in the period from February to August 2020. Researchers collected data from local and national nephrological and neurological registries and offered clinical and laboratory results from medical histories in follow-up periods.
RESULTS: This study enrolled 48 patients with a median age of 32.3 years (range, 18-46 years), and predominant female gender (60.45%). The percentage of patients with chronic kidney disease (CKD) diagnosis of the total number of patients was 66.90%, with end-stage renal disease development in 39.6%. The most prevalent renal lesions leading to chronic kidney disease were angiomyolipomas (AMLs) in 76.6%, while multiple renal cysts were present in 42.6% of patients. Nephrectomy was performed in 43% of patients, while the mTOR inhibitors were used in 18 patients (37.5%). The majority of patients had cutaneous manifestations of tuberous sclerosis-83.30% had hypomelanotic cutaneous lesions, and 68.80% had angiofibromas. Multiple retinal nodular hamartomas and "confetti" skin lesions were more frequent in end-stage renal disease (ESRD) than in patients with earlier stages of chronic kidney disease (p-0.033 and 0.03, respectively).
CONCLUSION: Our study has also shown that retinal hamartomas and "confetti" skin lesions are more frequent in end-stage renal diseases (ESRD) patients than in other chronic kidney disease (CKD) patients. Usage of mTOR inhibitors can also reduce the number of complications and associated with tuberous sclerosis, such as dermatological manifestations and retinal hamartoma, which are more common in the terminal stage of chronic kidney disease.

Keywords:  Chronic kidney disease; Retinal hamartoma; Skin lesions; TSC

DOI:  https://doi.org/10.1007/s11255-022-03352-9
Epilepsia. 2022 Aug 24.

GluN2C selective inhibition is a target to develop new antiepileptic compounds.

S Gataullina, G Galvani, S Touchet, C Nous, E Lemaire, J Laschet, C Chiron, O Dulac, E Dossi, J D Brion, S Messaoudi, M Alami, G Huberfeld.

  OBJECTIVE: Many early-onset epilepsies present as Developmental and Epileptic Encephalopathy associating refractory seizures, altered psychomotor development and disorganized interictal cortical activity. Abnormal upregulation of specific NMDA receptor subunits is being disentangled as one of the mechanisms of severe early-onset epilepsies. In Tuberous sclerosis complex, upregulation of the GluN2C subunit of the NMDA receptor with slow deactivation kinetic results in increased neuronal excitation and synchronization.METHODS: Starting from an available GluN2C/D antagonist, NMDA receptor modulating compounds were developed and screened using a patch clamp on neuronal culture in order to select those with the strongest inhibitory effect on glutamatergic NMDA currents. For these selected compounds, blood pharmacokinetics and passage through the blood-brain barrier were studied. We tested the effect of the most promising compounds on epileptic activity in Tsc1+/- mice brain slices with multielectrode array, then in vivo, at post-natal ages P14-P17, comparable to the usual age of epilepsy onset in humans.
RESULTS: Using a double electrode voltage clamp on isolated NMDA currents, we identified the most prominent antagonists of the GluN2C subunit with no effect on GluN2A as means of preventing side effects. The best compound passing through the blood-brain barrier was selected. Applied in vivo in 6 Tsc1+/- mice at P14-P17, this compound reduced or completely stopped spontaneous seizures in 4 of them, and decreased the background activity disorganization. Furthermore, ictal-like discharges stopped on a human brain sample from an infant with epilepsy due to TSC.
INTERPRETATION: Subunit-selective inhibition is a valuable target to develop drugs for severe epilepsies resulting from an upregulation of NMDA-receptor subunit-mediated transmission.

Keywords:  GluN2C NMDA-receptor subunit; Tuberous sclerosis complex; epilepsy

DOI:  https://doi.org/10.1111/epi.17396
Transl Psychiatry. 2022 Aug 31. 12(1): 355

The trilateral interactions between mammalian target of rapamycin (mTOR) signaling, the circadian clock, and psychiatric disorders: an emerging model.

Rubal Singla, Abhishek Mishra, Ruifeng Cao.

Circadian (~24 h) rhythms in physiology and behavior are evolutionarily conserved and found in almost all living organisms. The rhythms are endogenously driven by daily oscillatory activities of so-called "clock genes/proteins", which are widely distributed throughout the mammalian brain. Mammalian (mechanistic) target of rapamycin (mTOR) signaling is a fundamental intracellular signal transduction cascade that controls important neuronal processes including neurodevelopment, synaptic plasticity, metabolism, and aging. Dysregulation of the mTOR pathway is associated with psychiatric disorders including autism spectrum disorders (ASD) and mood disorders (MD), in which patients often exhibit disrupted daily physiological rhythms and abnormal circadian gene expression in the brain. Recent work has found that the activities of mTOR signaling are temporally controlled by the circadian clock and exhibit robust circadian oscillations in multiple systems. In the meantime, mTOR signaling regulates fundamental properties of the central and peripheral circadian clocks, including period length, entrainment, and synchronization. Whereas the underlying mechanisms remain to be fully elucidated, increasing clinical and preclinical evidence support significant crosstalk between mTOR signaling, the circadian clock, and psychiatric disorders. Here, we review recent progress in understanding the trilateral interactions and propose an "interaction triangle" model between mTOR signaling, the circadian clock, and psychiatric disorders (focusing on ASD and MD).

DOI: https://doi.org/10.1038/s41398-022-02120-8
J Biol Chem. 2022 Aug 27. pii: S0021-9258(22)00880-8. [Epub ahead of print] 102437

The RNA-binding protein AUF1 facilitates Akt phosphorylation at the membrane.

Mei-Ling Li, Aparna Ragupathi, Nikhil Patel, Tatiana Hernandez, Jedrick Magsino, Guy Werlen, Gary Brewer, Estela Jacinto.

  mTOR, which is part of mTOR complex 1 (mTORC1) and mTORC2, controls cellular metabolism in response to levels of nutrients and other growth signals. A hallmark of mTORC2 activation is the phosphorylation of Akt, which becomes upregulated in cancer. How mTORC2 modulates Akt phosphorylation remains poorly understood. Here, we found that the RNA binding protein, AUF1 (ARE/poly(U)-binding/degradation factor 1), modulates mTORC2/Akt signaling. We determined that AUF1 is required for phosphorylation of Akt at Thr308, Thr450, and Ser473, and that AUF1 also mediates phosphorylation of the mTORC2-modulated metabolic enzyme GFAT1 at Ser243. Additionally, AUF1 immunoprecipitation followed by qRT-PCR revealed that the mRNAs of Akt, GFAT1, and the mTORC2 component SIN1 associate with AUF1. Furthermore, expression of the p40 and p45, but not the p37 or p42, isoforms of AUF1 specifically mediate Akt phosphorylation. In the absence of AUF1, subcellular fractionation indicated that Akt fails to localize to the membrane. However, ectopic expression of a membrane-targeted allele of Akt is sufficient to allow Akt-Ser473 phosphorylation despite AUF1 depletion. Finally, conditions that enhance mTORC2 signaling, such as acute glutamine withdrawal augment AUF1 phosphorylation while mTOR inhibition abolishes AUF1 phosphorylation. Our findings unravel a role for AUF1 in promoting membrane localization of Akt to facilitate its phosphorylation on this cellular compartment. Targeting AUF1 could have therapeutic benefit for cancers with upregulated mTORC2/Akt signaling.

Keywords:  AUF1; Akt; RNA binding protein; glutamine; hnRNP D; mTOR; mTORC2

DOI:  https://doi.org/10.1016/j.jbc.2022.102437