bims-tubesc 2022-08-07 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2022–08–07
nine papers selected by

Sirolimus relieves seizures and neuropsychiatric symptoms via changes of microglial polarity in tuberous sclerosis complex model mice.
Convergence of Signaling Pathways in Mediating Actions of Leucine and IGF-1 on mTORC1 in L6 Myoblasts.
Genotype/phenotype correlation in 123 Chinese patients with Tuberous Sclerosis Complex.
Tuberous Sclerosis Complex With Multiple Organ Tumors: Case Report and Literature Review.
Subependymal giant-cell astrocytoma: a surgical review in the modern era of mTOR inhibitors.
Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms.
Birt-Hogg-Dubé Syndrome: Another mTOR Phenomenon.
Successful treatment with everolimus for severe heart failure with large cardiac rhabdomyomas.
Interactions between mTORC2 core subunits Rictor and mSin1 dictate selective and context-dependent phosphorylation of substrate kinases SGK1 and Akt.

Neuropharmacology. 2022 Aug 02. pii: S0028-3908(22)00262-3. [Epub ahead of print] 109203

Sirolimus relieves seizures and neuropsychiatric symptoms via changes of microglial polarity in tuberous sclerosis complex model mice.

Makiko Koike-Kumagai, Manabu Fujimoto, Mari Wataya-Kaneda.

  Tuberous sclerosis complex (TSC) is a genetic disorder involving a variety of physical manifestations, and is associated with epilepsy and multiple serious neuropsychiatric symptoms. These symptoms are collectively known as TSC-associated neuropsychiatric disorders (TAND), which is a severe burden for patients and their families. Overactivation of the mechanistic target of rapamycin complex 1 (mTORC1) by mutations in TSC1 or TSC2 is thought to cause TSC, and mTORC1 inhibitors such as sirolimus and everolimus are reported to be effective against various tumor types of TSC. However, there are various reports on the effect of mTORC1 inhibitor therapy on TAND in patients with TSC, which may or may not be effective. In our previous investigations, we generated TSC2 conditional knockout mice (Mitf-Cre, Tsc2 KO; Tsc2 cKO). These mice developed spontaneous epileptic activity. In the current study, we further analyzed the detailed behaviors of Tsc2 cKO mice and confirmed that they exhibited phenotypes of TAND as well as epileptic seizures, indicating that Tsc2 cKO mice are a useful model for TAND. Furthermore, the olfactory bulb and piriform cortex caused epilepsy and TAND in Tsc2 cKO mice, and neurodegeneration was observed. Immunohistology and immunophenotypic analysis of cells, and quantitative RT-PCR suggested that changes in microglial polarity were involved in the onset of TSC epilepsy and neuropsychiatric symptoms. Although the effect of mTORC1 inhibitors on TAND has not been established, the results of this study might help elucidate the mechanism of TAND pathogenesis and suggest that sirolimus may be a valuable therapeutic tool for TAND.

Keywords:  Epilepsy; Microglia polarity; Sirolimus; TSC-Associated neuropsychiatric disorders (TAND); Tuberous sclerosis complex (TSC)

DOI:  https://doi.org/10.1016/j.neuropharm.2022.109203
Am J Physiol Cell Physiol. 2022 Aug 01.

Convergence of Signaling Pathways in Mediating Actions of Leucine and IGF-1 on mTORC1 in L6 Myoblasts.

Paul A Roberson, Leonard S Jefferson, Scot R Kimball.

  Leucine and Insulin-like Growth Factor-1 (IGF-1) are important regulators of protein synthesis in skeletal muscle. The mechanistic target of rapamycin complex 1 (mTORC1) is of particular importance in their mechanism of action. In the present study, pathways through which leucine and IGF-1 converge to mediate activation of mTORC1 were examined in L6 myoblasts that were deprived of leucine and serum followed by readdition of either leucine or IGF-1. Compared to leucine- and serum-deprived myoblasts, IGF-1, but not leucine, promoted phosphorylation of Protein Kinase B (AKT), Tuberous Sclerosis Complex 2 (TSC2), and the autophosphorylation site on mTOR (S2481) and also stimulated mTOR kinase activity in mTOR immunoprecipitated samples. Both leucine and IGF-1 promoted phosphorylation of mTOR on S2448. The association of mTOR with the Regulatory Associated Protein of mTOR (Raptor) was altered by IGF-1 treatment and trended (p=0.065) to be altered by leucine treatment. Alterations in the association of mTOR with Raptor were proportional to changes in phosphorylation of the mTOR substrates, eIF4E-Binding Protein 1 (4E-BP1) and Ribosomal Protein S6 Kinase-β1 (p70S6K1). Surprisingly, leucine, but not IGF-1, stimulated protein synthesis suggesting a unique role for nutrients in regulating protein synthesis. Overall, the results are consistent with a model whereby IGF-1 stimulates phosphorylation of 4E-BP1 and p70S6K1 in L6 myoblasts through an AKT-TSC2-mTORC1 signaling pathway that also involves changes in the interaction between mTOR and Raptor. In contrast, leucine signaling to mTOR results in alterations in certain mTOR phosphorylation sites, the interaction between mTOR and Raptor, and stimulates protein synthesis.

Keywords:  Cellular Signaling; Metabolism; Protein Synthesis; Skeletal Muscle

DOI:  https://doi.org/10.1152/ajpcell.00183.2022
Eur J Med Genet. 2022 Jul 30. pii: S1769-7212(22)00154-9. [Epub ahead of print] 104573

Genotype/phenotype correlation in 123 Chinese patients with Tuberous Sclerosis Complex.

Samuel Yl Ng, Ho-Ming Luk, Edgar Wl Hau, Shirley Sw Cheng, Kris Pt Yu, Stephanie Ho, Myth Ts Mok, Ivan Fm Lo.

  Tuberous Sclerosis Complex (TSC) is a multisystemic neurocutaneous disorder with autosomal dominant inheritance. We performed mutational analyses on 123 Chinese patients with "definite TSC" according to the latest diagnostic criteria. Pathogenic/likely-pathogenic mutations were identified in 72.2% of all index patients (70/97), in which 35.7% (25/70) had TSC1 mutations and 64.3% (45/70) had TSC2 mutations. 84.5% (82/97) cases were sporadic and 15.5% (15/97) cases were familial. 62 unique variants were reported, in which 41.9% (26/62) were novel. Male patients had significantly more subependymal nodules (p = 0.029) than females, whereas renal angiomyolipoma (p = 0.032) occurred predominantly in females. Sporadic cases also had more renal angiomyolipoma (p = 0.004), cortical tubers (p = 0.008), hypopigmented macules (p = 0.018) and fibrous cephalic plaques (p = 0.028) than cases with known inheritance. Patients with TSC2 mutations were more likely to have mental retardation (p < 0.001), cardiac rhabdomyoma (p = 0.004), renal angiomyolipoma (p = 0.006) and facial angiofibromas (p = 0.026) than those with TSC1 mutations, while mutation-negative cases showed a mixed phenotype between those with TSC1 and TSC2 mutations. There were no significant phenotypic differences between patients with and without TSC1/TSC2 mutations, but TSC2 missense and in-frame mutations were associated with higher frequencies of mental retardation (P < 0.001), renal angiomyolipoma (p = 0.001), cardiac rhabdomyoma (p = 0.012) and facial angiofibroma (p = 0.021) than those with TSC1 frameshift and splice site mutations. Furthermore, a higher frequency of mental retardation (p = 0.013) was observed in patients with TSC2 missense and in-frame mutations than those with frameshift and splice site mutations. All 14 antenatal-onset patients had cardiac rhabdomyoma. Meanwhile, they had less seizures (p = 0.028) than those with paediatric-onset but had higher frequencies of mental retardation (p = 0.035) than those with adult-onset. Generally, paediatric-onset patients had more neurological manifestations, while initial presentations of adult-onset TSC were more diverse.

Keywords:  Genotype/phenotype correlations; Mutation analysis; Tuberous sclerosis complex

DOI:  https://doi.org/10.1016/j.ejmg.2022.104573
Front Oncol. 2022 ;12 916016

Tuberous Sclerosis Complex With Multiple Organ Tumors: Case Report and Literature Review.

Xinhe Zhang, Xinping Zhong, Xuyong Lin, Xuedan Li, Haoyu Tian, Bing Chang, Ying Wang, Jing Tong, Ningning Wang, Dan Li, Xiuli Jin, Die Huang, Yanmeng Wang, Huipeng Cui, Lin Guan, Yiling Li.

  Pancreatic neuroendocrine neoplasms (PNEN) are tumors that originate from neuroendocrine cells. Only about 1% patients are related to mutation of tuberous sclerosis complex gene. Here, we reported a rare case with involvement of multiple organs and space-occupying lesions. Initially, the patient was thought to have metastasis of a pancreatic tumor. However, the patient was diagnosed as pancreatic neuroendocrine tumors, liver perivascular epithelioid tumors, splenic hamartoma, and renal angiomyolipoma by pathological examination after surgery. We performed genetic mutation detection to identify that tuberous sclerosis complex 2 gene presented with a heterozygous variant. Tuberous sclerosis often presents with widespread tumors, but it is less common to present with pancreatic neuroendocrine tumors and liver perivascular tumors as highlighted in the case. So we analyzed the relationship between TSC gene mutations and related tumors. And we also reviewed the current molecular mechanisms and treatments for tuberous sclerosis complex.

Keywords:  liver perivascular epithelioid tumors; pancreatic neuroendocrine neoplasms; renal angiomyolipoma; splenic hamartoma; tuberous sclerosis complex

DOI:  https://doi.org/10.3389/fonc.2022.916016
Neurochirurgie. 2022 Jul 27. pii: S0028-3770(22)00112-6. [Epub ahead of print]

Subependymal giant-cell astrocytoma: a surgical review in the modern era of mTOR inhibitors.

G Danassegarane, J Tinois, Y Sahler, S Aouaissia, L Riffaud.

   INTRODUCTION: Surgical removal has been the historical treatment for subependymal giant-cell astrocytoma (SEGA) in tuberous sclerosis complex (TSC) patients. In the past decade, mTOR inhibitors have shown efficacy in the treatment of SEGA, significantly reducing tumor size. The aim of this study was to assess the safety and efficacy of surgical treatment at a time when mTOR inhibitors have changed standard treatment.
MATERIAL AND METHODS: We conducted a single-center retrospective study including all patients treated by surgery for SEGA from October 2003 to September 2019, with a review of all SEGA surgical case series, following PRISMA guidelines. Research focused on demographics, surgical indications, surgical approach, use of CSF shunt, morbidity and mortality, resection quality, recurrence rate and treatment of recurrence, follow-up and long-term clinical status.
RESULTS: Eleven patients were included, with a median age at surgery of 16.0 years. Gross total resection was achieved in 8 patients (72%), with no permanent morbidity. One patient needed further surgery for tumor recurrence. Eighteen studies were reviewed, totaling 263 TSC patients affected by SEGA and 286 surgical procedures. Gross total resection was achieved in 81.1% of cases, mortality was 4.9% and permanent morbidity 6.1%. Tumor recurrence occurred in 11.5% of cases, and was secondary to partial tumor resection at first surgery in the majority of cases.
CONCLUSION: Surgical treatment of SEGA is still a valid and effective option. Morbidity is low and complete disappearance of SEGA can be achieved in selected cases.

Keywords:  Everolimus; Subependymal giant cell astrocytoma; Tuberous sclerosis complex; Tumor surgery; mTOR inhibitors

DOI:  https://doi.org/10.1016/j.neuchi.2022.07.003
Front Aging Neurosci. 2022 ;14 903973

Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms.

Kaylin Hwang, Rahil N Vaknalli, Kwaku Addo-Osafo, Mariane Vicente, Keith Vossel.

  Tau is a microtubule-associated protein known to bind and promote assembly of microtubules in neurons under physiological conditions. However, under pathological conditions, aggregation of hyperphosphorylated tau causes neuronal toxicity, neurodegeneration, and resulting tauopathies like Alzheimer's disease (AD). Clinically, patients with tauopathies present with either dementia, movement disorders, or a combination of both. The deposition of hyperphosphorylated tau in the brain is also associated with epilepsy and network hyperexcitability in a variety of neurological diseases. Furthermore, pharmacological and genetic targeting of tau-based mechanisms can have anti-seizure effects. Suppressing tau phosphorylation decreases seizure activity in acquired epilepsy models while reducing or ablating tau attenuates network hyperexcitability in both Alzheimer's and epilepsy models. However, it remains unclear whether tauopathy and epilepsy comorbidities are mediated by convergent mechanisms occurring upstream of epileptogenesis and tau aggregation, by feedforward mechanisms between the two, or simply by coincident processes. In this review, we investigate the relationship between tauopathies and seizure disorders, including temporal lobe epilepsy (TLE), post-traumatic epilepsy (PTE), autism spectrum disorder (ASD), Dravet syndrome, Nodding syndrome, Niemann-Pick type C disease (NPC), Lafora disease, focal cortical dysplasia, and tuberous sclerosis complex. We also explore potential mechanisms implicating the role of tau kinases and phosphatases as well as the mammalian target of rapamycin (mTOR) in the promotion of co-pathology. Understanding the role of these co-pathologies could lead to new insights and therapies targeting both epileptogenic mechanisms and cognitive decline.

Keywords:  cognitive decline; epilepsy; hyperexcitability; hyperphosphorylation of tau; mTOR; tau

DOI:  https://doi.org/10.3389/fnagi.2022.903973
Clin Dermatol. 2022 Jul 27. pii: S0738-081X(22)00104-3. [Epub ahead of print]

Birt-Hogg-Dubé Syndrome: Another mTOR Phenomenon.

Rohan R Shah, W Clark Lambert, Robert A Schwartz.

  Birt-Hogg-Dubé syndrome is an uncommon autosomal dominant systemic disorder with cutaneous findings notable for fibrofolliculomas or trichodiscomas on the scalp, face, neck, and trunk. These cutaneous signs are associated with bilateral renal cell carcinoma, benign renal cysts, pulmonary cysts, and spontaneous pneumothorax. Given its autosomal dominant inheritance pattern, the successful diagnosis of BHDS may elucidate a diagnosis in family members. BHDS results from a mutation in the FLCN gene encoding the folliculin protein, a transcriptional regulator of the mammalian target of rapamycin (mTOR) signaling pathway. Like tuberous sclerosis, BHDS's clinical features may subside with the use of oral rapamycin for mTOR inhibition, a theoretical concept meriting exploration. Although its prevalence in the general population has been estimated at only 2 cases per million, BHDS has been detected in a few patients from the nearby Portuguese-lineage quarter of the city of Newark, a disproportionate prevalence possibly explained by the founder effect.

Keywords:  Birt-Hogg-Dubé; Hornstein-Knickenburg; fibrofolliculomas; founder effect; mTOR; pneumothorax; rapamycin; trichodiscomas

DOI:  https://doi.org/10.1016/j.clindermatol.2022.07.014
Pediatr Int. 2022 01;64(1): e15219

Successful treatment with everolimus for severe heart failure with large cardiac rhabdomyomas.

Shutaro Inoue, Ryo Inuzuka, Satsuki Kakiuchi, Atsushi Sato, Hikoro Matsui.



Keywords:  cardiac rhabdomyoma; complication; everolimus; heart failure; tuberous sclerosis

DOI:  https://doi.org/10.1111/ped.15219
J Biol Chem. 2022 Aug 01. pii: S0021-9258(22)00730-X. [Epub ahead of print] 102288

Interactions between mTORC2 core subunits Rictor and mSin1 dictate selective and context-dependent phosphorylation of substrate kinases SGK1 and Akt.

Zanlin Yu, Junliang Chen, Enzo Takagi, Feng Wang, Bidisha Saha, Xi Liu, Lydia-Marie Joubert, Catherine E Gleason, Mingliang Jin, Chengmin Li, Carlos Nowotny, David Agard, Yifan Cheng, David Pearce.

Mechanistic target of rapamycin complex 2 (mTORC2) is a multi-subunit kinase complex, central to multiple essential signaling pathways. Two core subunits, Rictor and mSin1, distinguish it from the related mTORC1 and support context-dependent phosphorylation of its substrates. mTORC2 structures have been determined previously, however, important questions remain, particularly regarding the structural determinants mediating substrate specificity and context-dependent activity. Here, we used cryo-EM to obtain high-resolution structures of the human mTORC2 apo-complex in the presence of substrates Akt and SGK1. Using functional assays, we then tested predictions suggested by substrate-induced structural changes in mTORC2. For the first time, we visualized in the apo-state the side chain interactions between Rictor and mTOR that sterically occlude recruitment of mTORC1 substrates and confer resistance to the mTORC1 inhibitor rapamycin. Also in the apo-state, we observed that mSin1 formed extensive contacts with Rictor via a pair of short α-helices nestled between two Rictor helical repeat clusters, as well as by an extended strand that makes multiple weak contacts with Rictor helical cluster 1. In co-complex structures, we found that SGK1, but not Akt, markedly altered the conformation of the mSin1 N-terminal extended strand, disrupting multiple weak interactions while inducing a large rotation of mSin1 residue Arg-83, which then interacts with a patch of negatively charged residues within Rictor. Finally, we demonstrate mutation of Arg-83 to Ala selectively disrupts mTORC2-dependent phosphorylation of SGK1, but not of Akt, supporting context-dependent substrate selection. These findings provide new structural and functional insights into mTORC2 specificity and context-dependent activity.

DOI: https://doi.org/10.1016/j.jbc.2022.102288