mTOR Signaling and Neural Stem Cells: The Tuberous Sclerosis Complex Model

Polchi, Alice; Magini, Alessandro; Meo, Danila Di; Tancini, Brunella; Emiliani, Carla

doi:10.3390/ijms19051474

Cited by 15 publications

(7 citation statements)

References 164 publications

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“…Therefore, to mimic the adaptive responses seen in PRs of AMD patients and study their effect on retinal and RPE health, we generated a mouse model with constitutive activation mTORC1 in PRs of wild-type mice. This was achieved by deletion of the tuberous sclerosis complex 1 (Tsc1) gene, a negative regulator of mTORC1 (27). We found an age-and mTORC1-dependent onset of advanced AMD pathologies, including GA and neovascular pathologies, at a frequency similar to that seen in humans (2).…”

Section: Significancementioning

confidence: 80%

Altered photoreceptor metabolism in mouse causes late stage age-related macular degeneration-like pathologies

Cheng

Cipi

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. While the histopathology of the different disease stages is well characterized, the cause underlying the progression, from the early drusen stage to the advanced macular degeneration stage that leads to blindness, remains unknown. Here, we show that photoreceptors (PRs) of diseased individuals display increased expression of two key glycolytic genes, suggestive of a glucose shortage during disease. Mimicking aspects of this metabolic profile in PRs of wild-type mice by activation of the mammalian target of rapamycin complex 1 (mTORC1) caused early drusen-like pathologies, as well as advanced AMD-like pathologies. Mice with activated mTORC1 in PRs also displayed other early disease features, such as a delay in photoreceptor outer segment (POS) clearance and accumulation of lipofuscin in the retinal-pigmented epithelium (RPE) and of lipoproteins at the Bruch’s membrane (BrM), as well as changes in complement accumulation. Interestingly, formation of drusen-like deposits was dependent on activation of mTORC1 in cones. Both major types of advanced AMD pathologies, including geographic atrophy (GA) and neovascular pathologies, were also seen. Finally, activated mTORC1 in PRs resulted in a threefold reduction in di-docosahexaenoic acid (DHA)–containing phospholipid species. Feeding mice a DHA-enriched diet alleviated most pathologies. The data recapitulate many aspects of the human disease, suggesting that metabolic adaptations in photoreceptors could contribute to disease progression in AMD. Identifying the changes downstream of mTORC1 that lead to advanced pathologies in mouse might present new opportunities to study the role of PRs in AMD pathogenesis.

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Section: Significancementioning

confidence: 80%

Altered photoreceptor metabolism in mouse causes late stage age-related macular degeneration-like pathologies

Cheng

Cipi

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…In TSC patients, germ line and somatic dominant loss of function mutations in the genes encoding hamartin (TSC1) or tuberin (TSC2) can cause the development of benign tumors and, abnormally differentiated cortical neuronal progenitors that may cause focal seizures (11). Tuberin and harmatin are components of a complex that regulates the activity of the protein kinase, mTOR (12). Similarly, FCD and HME can be caused by activating somatic mutations in the MTOR gene, and in genes that regulate mTOR activity (13–15).…”

Section: Introductionmentioning

confidence: 99%

Evidence for Innate and Adaptive Immune Responses in a Cohort of Intractable Pediatric Epilepsy Surgery Patients

et al. 2019

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Brain-infiltrating lymphocytes (BILs) were isolated from resected brain tissue from 10 pediatric epilepsy patients who had undergone surgery for Hemimegalencephaly (HME) (n = 1), Tuberous sclerosis complex (TSC) (n = 2), Focal cortical dysplasia (FCD) (n = 4), and Rasmussen encephalitis (RE) (n = 3). Peripheral blood mononuclear cells (PBMCs) were also isolated from blood collected at the time of the surgery. Cells were immunostained with a panel of 20 antibody markers, and analyzed by mass cytometry. To identify and quantify the immune cell types in the samples, an unbiased clustering method was applied to the entire data set. More than 85 percent of the CD45+ cells isolated from resected RE brain tissue comprised T cells; by contrast NK cells and myeloid cells constituted 80–95 percent of the CD45+ cells isolated from the TSC and the FCD brain specimens. Three populations of myeloid cells made up >50 percent of all of the myeloid cells in all of the samples of which a population of HLA-DR+ CD11b+ CD4− cells comprised the vast majority of myeloid cells in the BIL fractions from the FCD and TSC cases. CD45RA+ HLA-DR− CD11b+ CD16+ NK cells constituted the major population of NK cells in the blood from all of the cases. This subset also comprised the majority of NK cells in BILs from the resected RE and HME brain tissue, whereas NK cells defined as CD45RA− HLA-DR+ CD11b− CD16− cells comprised 86–96 percent of the NK cells isolated from the FCD and TSC brain tissue. Thirteen different subsets of CD4 and CD8 αβ T cells and γδ T cells accounted for over 80% of the CD3+ T cells in all of the BIL and PBMC samples. At least 90 percent of the T cells in the RE BILs, 80 percent of the T cells in the HME BILs and 40–66 percent in the TSC and FCD BILs comprised activated antigen-experienced (CD45RO+ HLA-DR+ CD69+) T cells. We conclude that even in cases where there is no evidence for an infection or an immune disorder, activated peripheral immune cells may be present in epileptogenic areas of the brain, possibly in response to seizure-driven brain inflammation.

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“…Key signaling molecules/pathways References Angiogenesis -Hypoxia-Inducible Factors (HIFs) (Semenza, 2014(Semenza, , 2020Abeyrathna and Su, 2015) -VEGF/NOTCH signaling (Jakobsson et al, 2010;Walchli et al, 2015;Paredes et al, 2018) -WNT/ß-catenin signaling (Martowicz et al, 2019) -Non-canonical WNT ligands (Korn et al, 2014) -Unfolded Protein Response (UPR) signaling Zhuang et al (2017) -Nuclear Factor-Kappa B (NF-kB) (Tabruyn and Griffioen, 2008;Binet and Sapieha, 2015) BBB Neurogenesis -WNT signaling pathway (Coullery et al, 2016;Arredondo et al, 2020) -AKT/mTOR pathway (Götz and Huttner, 2005;Abe et al, 2010;Polchi et al, 2018) -Nuclear Factor-Kappa B (NF-kB) (Y. Zhang and Hu, 2012) -Unfolded Protein Response (UPR) signaling (Shim et al, 2004;Hayashi et al, 2008;Murao and Nishitoh, 2017) Frontiers in Cell and Developmental Biology frontiersin.org formation and maintenance; HIF, VEGFA, and NOTCH crossregulate each other in angiogenesis; ROS, WNT, and UPR promote neurogenesis; to mention only a few interactions (Table 1).…”

Section: Processmentioning

confidence: 99%

It takes two to tango: Widening our understanding of the onset of schizophrenia from a neuro-angiogenic perspective

Casas

Arancibia-Altamirano

Rosa

et al. 2022

Front. Cell Dev. Biol.

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Schizophrenia is a chronic debilitating mental disorder characterized by perturbations in thinking, perception, and behavior, along with brain connectivity deficiencies, neurotransmitter dysfunctions, and loss of gray brain matter. To date, schizophrenia has no cure and pharmacological treatments are only partially efficacious, with about 30% of patients describing little to no improvement after treatment. As in most neurological disorders, the main descriptions of schizophrenia physiopathology have been focused on neural network deficiencies. However, to sustain proper neural activity in the brain, another, no less important network is operating: the vast, complex and fascinating vascular network. Increasing research has characterized schizophrenia as a systemic disease where vascular involvement is important. Several neuro-angiogenic pathway disturbances have been related to schizophrenia. Alterations, ranging from genetic polymorphisms, mRNA, and protein alterations to microRNA and abnormal metabolite processing, have been evaluated in plasma, post-mortem brain, animal models, and patient-derived induced pluripotent stem cell (hiPSC) models. During embryonic brain development, the coordinated formation of blood vessels parallels neuro/gliogenesis and results in the structuration of the neurovascular niche, which brings together physical and molecular signals from both systems conforming to the Blood-Brain barrier. In this review, we offer an upfront perspective on distinctive angiogenic and neurogenic signaling pathways that might be involved in the biological causality of schizophrenia. We analyze the role of pivotal angiogenic-related pathways such as Vascular Endothelial Growth Factor and HIF signaling related to hypoxia and oxidative stress events; classic developmental pathways such as the NOTCH pathway, metabolic pathways such as the mTOR/AKT cascade; emerging neuroinflammation, and neurodegenerative processes such as UPR, and also discuss non-canonic angiogenic/axonal guidance factor signaling. Considering that all of the mentioned above pathways converge at the Blood-Brain barrier, reported neurovascular alterations could have deleterious repercussions on overall brain functioning in schizophrenia.

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mTOR Signaling and Neural Stem Cells: The Tuberous Sclerosis Complex Model

Cited by 15 publications

References 164 publications

Altered photoreceptor metabolism in mouse causes late stage age-related macular degeneration-like pathologies

Altered photoreceptor metabolism in mouse causes late stage age-related macular degeneration-like pathologies

Evidence for Innate and Adaptive Immune Responses in a Cohort of Intractable Pediatric Epilepsy Surgery Patients

It takes two to tango: Widening our understanding of the onset of schizophrenia from a neuro-angiogenic perspective

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