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Integrated multi-omics reveals mTOR-LPL-driven dysregulated lipid metabolism induces neuronal hyperexcitability in human microglia of tuberous sclerosis complex

ABSTRACT: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by heterozygous pathogenic variants in either TSC1 or TSC2. Emerging evidence suggests a connection between microglia activation and epilepsy as well as cognitive impairment in TSC patients. However, the impact of the causal variants of TSC1/2 genes on human microglia and their contribution to TSC's neurological symptoms remain largely unexplored. In this study, we generated human microglia from induced pluripotent stem cells (iPSCs) from a TSC patient cohort. Through extensive molecular and cellular analysis of TSC microglia, including transcriptomics, proteomics/phosphopreteomics, and lipidomics, we found that heterozygous TSC2 pathogenic variants were sufficient to cause aberrant lipid metabolism marked by increased glycerophosphocholines and fatty acyls. These metabolic changes resulted in enhanced phagocytosis and inflammation. Strikingly, the dysregulated lipid metabolism in TSC microglia is driven by a hyper-activated mTOR-lipoprotein lipase (LPL) pathway. Further, cellular and electrophysiological assessments of neuron/microglia co-cultures revealed that TSC microglia directly affect neuronal development, excitability, and neuronal network activity, which could be largely ameliorated by mTOR/LPL inhibition. Collectively, our research unveiled the molecular and cellular abnormalities in TSC microglia affecting neuronal development and function, and highlighted the mTOR-LPL pathway as a novel potential therapeutic target for the neuropathology of TSC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244091 | GEO | 2023/09/27

REPOSITORIES: GEO

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Project description:DallePezze2012 - TSC-independent mTORC2 regulation This model is described in the article: A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Dalle Pezze P, Sonntag AG, Thien A, Prentzell MT, Gödel M, Fischer S, Neumann-Haefelin E, Huber TB, Baumeister R, Shanley DP, Thedieck K. Sci Signal 2012 Mar; 5(217): ra25 Abstract: The kinase mammalian target of rapamycin (mTOR) exists in two multiprotein complexes (mTORC1 and mTORC2) and is a central regulator of growth and metabolism. Insulin activation of mTORC1, mediated by phosphoinositide 3-kinase (PI3K), Akt, and the inhibitory tuberous sclerosis complex 1/2 (TSC1-TSC2), initiates a negative feedback loop that ultimately inhibits PI3K. We present a data-driven dynamic insulin-mTOR network model that integrates the entire core network and used this model to investigate the less well understood mechanisms by which insulin regulates mTORC2. By analyzing the effects of perturbations targeting several levels within the network in silico and experimentally, we found that, in contrast to current hypotheses, the TSC1-TSC2 complex was not a direct or indirect (acting through the negative feedback loop) regulator of mTORC2. Although mTORC2 activation required active PI3K, this was not affected by the negative feedback loop. Therefore, we propose an mTORC2 activation pathway through a PI3K variant that is insensitive to the negative feedback loop that regulates mTORC1. This putative pathway predicts that mTORC2 would be refractory to Akt, which inhibits TSC1-TSC2, and, indeed, we found that mTORC2 was insensitive to constitutive Akt activation in several cell types. Our results suggest that a previously unknown network structure connects mTORC2 to its upstream cues and clarifies which molecular connectors contribute to mTORC2 activation. This model is hosted on BioModels Database and identified by: BIOMD0000000581. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Patients with tuberous sclerosis complex (TSC) develop hamartomas containing biallelic inactivating mutations in either TSC1 or TSC2, resulting in mammalian target of rapamycin (mTOR) activation. Hamartomas overgrow epithelial and mesenchymal cells in TSC skin. The pathogenetic mechanisms for these changes had not been investigated, and the existence or location of cells with biallelic mutations (âtwo-hitâ cells) that resulted in mTOR activation was unclear. We compared TSC skin hamartomas (facial angiofibromas and periungual fibromas) to normal-appearing skin of the same patient, and observed more proliferation and mTOR activation in hamartoma epidermis. âTwo-hitâ cells were not detected in the epidermis. Fibroblast-like cells in the dermis, however, exhibited allelic deletion of TSC2, in both touch preparations of fresh tumor samples and cells grown from TSC skin tumors, suggesting that increased epidermal proliferation and mTOR activation were not caused by second-hit mutations in the keratinocytes but by mesenchymal-epithelial interactions. Gene expression arrays, used to identify potential paracrine factors released by mesenchymal cells, revealed more epiregulin mRNA in fibroblast-like angiofibroma and periungual fibroma cells than in fibroblasts from normal-appearing skin of the same patient. Elevation of epiregulin mRNA was confirmed using real-time PCR, and increased amounts of epiregulin protein were demonstrated using immunoprecipitation and ELISA. Epiregulin stimulated keratinocyte proliferation and phosphorylation of ribosomal protein S6 in vitro. These results suggest that hamartomatous TSC skin tumors are induced by paracrine factors released by âtwo-hitâ cells in the dermis, and that proliferation with mTOR activation of the overlying epidermis is an effect of epiregulin. Experiment Overall Design: The study is of case/control design with biological replication. Tumor (case) and normal (control) fibroblast cells were isolated from each of four patients (biological replicates).

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Integrated multi-omics reveals mTOR-LPL-driven dysregulated lipid metabolism induces neuronal hyperexcitability in human microglia of tuberous sclerosis complex

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