Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse
| Autor: | 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 |
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| Přispěvatelé: | 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 |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | 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 |
| ISSN: | 1532-8600 0026-0495 |
| DOI: | 10.1016/j.metabol.2020.154463 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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