A microglial cell model for acyl-CoA oxidase 1 deficiency
| Autor: | Mustapha Cherkaoui-Malki, Michel Jadot, Stéphane Savary, Quentin Raas, Yannick Hamon, Catherine Gondcaille, Valerio Leoni, Claudio Caccia, Franck Ménétrier, Doriane Trompier, Boubker Nasser, Gérard Lizard, Pierre Andreoletti, Fatima-Ezzahra Saih |
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| Přispěvatelé: | Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Sol Agro et hydrosystème Spatialisation (SAS), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Laboratoire de Biochimie, Faculté des Sciences et Techniques [Settat] (FSTS), Université Hassan 1er [Settat]-Université Hassan 1er [Settat], PROSITON, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), AGroécologie, Innovations, teRritoires (AGIR), Institut National de la Recherche Agronomique (INRA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT), Raas, Q, Saih, F, Gondcaille, C, Trompier, D, Hamon, Y, Leoni, V, Caccia, C, Nasser, B, Jadot, M, Ménétrier, F, Lizard, G, Cherkaoui-Malki, M, Andreoletti, P, Savary, S |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Acyl-CoA oxidase Cell Mitochondrion Peroxisome Models Biological Cell Line Microglia/cytology 03 medical and health sciences Mice 0302 clinical medicine VLCFA Models Lipid droplet Unsaturated/metabolism medicine Neurodegenerative Diseases/genetics Animals Molecular Biology Hydrogen Peroxide/metabolism Cell Proliferation Gene Editing Cell growth Chemistry Fatty Acids peroxisme Neurodegenerative Diseases Hydrogen Peroxide Cell Biology Acyl-CoA Oxidase/deficiency Biological 3. Good health Cell biology Fatty Acids/metabolism Oxidative Stress 030104 developmental biology medicine.anatomical_structure Cell culture Mutation Fatty Acids Unsaturated ACOX1 [SDV.IMM]Life Sciences [q-bio]/Immunology Microglia CRISPR-Cas Systems 030217 neurology & neurosurgery |
| Zdroj: | Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids, 2019, 1864 (4), pp.567-576. ⟨10.1016/j.bbalip.2018.10.005⟩ Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids, Elsevier, 2019, 1864 (4), pp.567-576. ⟨10.1016/j.bbalip.2018.10.005⟩ Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids, 2019, 1864 (4), pp.567-576. ⟨10.1016/j.bbalip.2018.10.005⟩ |
| ISSN: | 1388-1981 |
| DOI: | 10.1016/j.bbalip.2018.10.005⟩ |
| Popis: | Acyl-CoA oxidase 1 (ACOX1) deficiency is a rare and severe peroxisomal leukodystrophy associated with a very long-chain fatty acid (VLCFA) β–oxidation defect. This neurodegenerative disease lacks relevant cell models to further decipher the pathomechanisms in order to identify novel therapeutic targets. Since peroxisomal defects in microglia appear to be a key component of peroxisomal leukodystrophies, we targeted the Acox1 gene in the murine microglial BV-2 cell line. Using CRISPR/Cas9 gene editing, we generated an Acox1-deficient cell line and validated the allelic mutations, which lead to the absence of ACOX1 protein and enzymatic activity. The activity of catalase, the enzyme degrading H 2O 2, was increased, likely in response to the alteration of redox homeostasis. The mutant cell line grew more slowly than control cells without obvious morphological changes. However, ultrastructural analysis revealed an increased number of peroxisomes and mitochondria associated with size reduction of mitochondria. Changes in the distribution of lipid droplets containing neutral lipids have been observed in mutant cells; lipid analysis revealed the accumulation of saturated and monounsaturated VLCFA. Besides, expression levels of genes encoding interleukin-1 beta and 6 (IL-1β and IL-6), as well as triggering receptor expressed on myeloid cells 2 (Trem2) were found modified in the mutant cells suggesting modification of microglial polarization and phagocytosis ability. In summary, this Acox1-deficient cell line presents the main biochemical characteristics of the human disease and will serve as a promising model to further investigate the consequences of a specific microglial peroxisomal β–oxidation defect on oxidative stress, inflammation and cellular functions. |
| Databáze: | OpenAIRE |
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