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Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse

التفاصيل البيبلوغرافية
العنوان: Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse
المؤلفون: Maja Malnar, Angela Bachi, Helena H. Chowdhury, Anemari Horvat, Patrizia D’Adamo, Antonia Gurgone, Saša Trkov Bobnar, Marko Muhič, Lorenzo Piemonti, Maria Lidia Mignogna, Michela Masetti, Jelena Velebit, Veronica Bianchi, Robert Zorec, Matjaž Stenovec, Alessia Mercalli, Katja Fink, Sara Belloli, Stefano Taverna, Maja Potokar, Marko Kreft, Rosa Maria Moresco, Nina Vardjan, Maddalena Ripamonti, Umberto Restuccia
المساهمون: D'Adamo, Patrizia, Horvat, Anemari, Gurgone, Antonia, Mignogna, Maria Lidia, Bianchi, Veronica, Masetti, Michela, Ripamonti, Maddalena, Taverna, Stefano, Velebit, Jelena, Malnar, Maja, Muhič, Marko, Fink, Katja, Bachi, Angela, Restuccia, Umberto, Belloli, Sara, Moresco, Rosa Maria, Mercalli, Alessia, Piemonti, Lorenzo, Potokar, Maja, Bobnar, Saša Trkov, Kreft, Marko, Chowdhury, Helena H, Stenovec, Matjaž, Vardjan, Nina, Zorec, R, D'Adamo, P, Horvat, A, Gurgone, A, Mignogna, M, Bianchi, V, Masetti, M, Ripamonti, M, Taverna, S, Velebit, J, Malnar, M, Muhic, M, Fink, K, Bachi, A, Restuccia, U, Belloli, S, Moresco, R, Mercalli, A, Piemonti, L, Potokar, M, Bobnar, S, Kreft, M, Chowdhury, H, Stenovec, M, Vardjan, N
المصدر: Metabolism
Metabolism, clinical and experimental
116 (2021): 154463. doi:10.1016/j.metabol.2020.154463
info:cnr-pdr/source/autori:D'Adamo P.; Horvat A.; Gurgone A.; Mignogna M.L.; Bianchi V.; Masetti M.; Ripamonti M.; Taverna S.; Velebit J.; Malnar M.; Muhic M.; Fink K.; Bachi A.; Restuccia U.; Belloli S.; Moresco R.M.; Mercalli A.; Piemonti L.; Potokar M.; Bobnar S.T.; Kreft M.; Chowdhury H.H.; Stenovec M.; Vardjan N.; Zorec R./titolo:Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse/doi:10.1016%2Fj.metabol.2020.154463/rivista:Metabolism, clinical and experimental (Print)/anno:2021/pagina_da:154463/pagina_a:/intervallo_pagine:154463/volume:116
بيانات النشر: W.B. Saunders, 2021.
سنة النشر: 2021
مصطلحات موضوعية: 0301 basic medicine, CTX, context memory, Male, Endocrinology, Diabetes and Metabolism, Glucose uptake, Intellectual disability, FRET, Förster Resonance Energy Transfer, SV, synaptic vesicle, XLID, X-linked intellectual disability, Mice, 0302 clinical medicine, Endocrinology, Basic Science, GDI1 knockout mice, Aerobic glycolysis, Astrocytes, cAMP, Glycolysis, Gdi1 KO, full knockout of Gdi1, Cells, Cultured, Guanine Nucleotide Dissociation Inhibitors, NA, noradrenaline, Mice, Knockout, Cultured, 3-Cl-5-OH-BA, 3-chloro-5-hydroxybenzoic acid, Animals, Brain, Deoxyglucose, Down-Regulation, Glucose, Intellectual Disability, Maze Learning, Memory, Memory Disorders, [18F]-FDG, [18F]-fluoro-2-deoxy-d-glucose, Aerobic glycolysi, cAMP, cyclic adenosine monophosphate, GlastGdi1flox/Y, GLAST:CreERT2+/Gdi1lox/Y inducible astrocyte-specific Gdi1 KO male mice, medicine.anatomical_structure, intellectual disability, Knockout mouse, Astrocyte, Gdi1 WT, wild type, medicine.medical_specialty, Cells, Knockout, 030209 endocrinology & metabolism, Biology, 2-DG, 2-deoxy-d-glucose, sEPSCs, spontaneous excitatory postsynaptic currents, CNS, central nervous system, SEM, standard error of the mean, 03 medical and health sciences, αGDI, α guanosine dissociation inhibitor protein coded by GDI1 gene, CFP, cyan fluorescent protein, Downregulation and upregulation, Internal medicine, medicine, aerobic glycolysis, GlastGdi1X/Y, male mice (Gdi1X/Y) carrying the GLAST:CreERT2 transgene, GLUT1, d-glucose transporter, Wild type, astrocytes, GFAP, glial fibrillary acidic protein, PSD, postsynaptic density, GDI1, guanosine dissociation inhibitor 1 gene, YFP, yellow fluorescent protein, 030104 developmental biology, GPCR, G-protein coupled receptor, Anaerobic glycolysis, GPR81, G-protein receptor 81, CS, conditional stimulus, tone, PKA, protein kinase A, MCTs, monocarboxylate transporters, Homeostasis
الوصف: Objectives GDI1 gene encodes for αGDI, a protein controlling the cycling of small GTPases, reputed to orchestrate vesicle trafficking. Mutations in human GDI1 are responsible for intellectual disability (ID). In mice with ablated Gdi1, a model of ID, impaired working and associative short-term memory was recorded. This cognitive phenotype worsens if the deletion of αGDI expression is restricted to neurons. However, whether astrocytes, key homeostasis providing neuroglial cells, supporting neurons via aerobic glycolysis, contribute to this cognitive impairment is unclear. Methods We carried out proteomic analysis and monitored [18F]-fluoro-2-deoxy-d-glucose uptake into brain slices of Gdi1 knockout and wild type control mice. d-Glucose utilization at single astrocyte level was measured by the Förster Resonance Energy Transfer (FRET)-based measurements of cytosolic cyclic AMP, d-glucose and L-lactate, evoked by agonists selective for noradrenaline and L-lactate receptors. To test the role of astrocyte-resident processes in disease phenotype, we generated an inducible Gdi1 knockout mouse carrying the Gdi1 deletion only in adult astrocytes and conducted behavioural tests. Results Proteomic analysis revealed significant changes in astrocyte-resident glycolytic enzymes. Imaging [18F]-fluoro-2-deoxy-d-glucose revealed an increased d-glucose uptake in Gdi1 knockout tissue versus wild type control mice, consistent with the facilitated d-glucose uptake determined by FRET measurements. In mice with Gdi1 deletion restricted to astrocytes, a selective and significant impairment in working memory was recorded, which was rescued by inhibiting glycolysis by 2-deoxy-d-glucose injection. Conclusions These results reveal a new astrocyte-based mechanism in neurodevelopmental disorders and open a novel therapeutic opportunity of targeting aerobic glycolysis, advocating a change in clinical practice.
Highlights • Mutations in human Gdi1, encoding αGDI, a protein controlling vesicle traffic, are responsible for Intellectual Disability. • Gdi1 knockout revealed significant changes in astrocyte-resident glycolytic enzymes and facilitated D-glucose utilization. • Astrocyte-selective Gdi1 deletion impairs working memory, which can be rescued by administration of 2-deoxy-D-glucose. • Astrocyte-based glycolysis is a new target to treat Intellectual Disability.
اللغة: English
تدمد: 1532-8600
0026-0495
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c2b634b090f73e01f5e64f5a419978ac
http://europepmc.org/articles/PMC7871014
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....c2b634b090f73e01f5e64f5a419978ac
قاعدة البيانات: OpenAIRE
الوصف
تدمد:15328600
00260495