دورية أكاديمية
Cholesterol redistribution triggered by CYP46A1 gene therapy improves major hallmarks of Niemann-Pick type C disease but is not sufficient to halt neurodegeneration.
| العنوان: | Cholesterol redistribution triggered by CYP46A1 gene therapy improves major hallmarks of Niemann-Pick type C disease but is not sufficient to halt neurodegeneration. |
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| المؤلفون: | Nunes MJ; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Carvalho AN; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Reis J; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Costa D; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Moutinho M; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Mateus J; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal., Mendes de Almeida R; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Brito S; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Risso D; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Nunes S; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Castro-Caldas M; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; Department of Life Sciences, Faculty of Science and Technology, Universidade NOVA de Lisboa, Caparica, Portugal., Gama MJ; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Rodrigues CMP; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Xapelli S; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal., Diógenes MJ; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal., Cartier N; NeuroGenCell, INSERM U1127, Paris Brain Institute (ICM), Sorbonne University, CNRS, APHP, University Hospital Pitié Salpêtrière, Paris, France., Chali F; NeuroGenCell, INSERM U1127, Paris Brain Institute (ICM), Sorbonne University, CNRS, APHP, University Hospital Pitié Salpêtrière, Paris, France., Piguet F; NeuroGenCell, INSERM U1127, Paris Brain Institute (ICM), Sorbonne University, CNRS, APHP, University Hospital Pitié Salpêtrière, Paris, France., Rodrigues E; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. Electronic address: Elsa.Rodrigues@ff.ulisboa.pt. |
| المصدر: | Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2024 Mar; Vol. 1870 (3), pp. 166993. Date of Electronic Publication: 2023 Dec 22. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101731730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-260X (Electronic) Linking ISSN: 09254439 NLM ISO Abbreviation: Biochim Biophys Acta Mol Basis Dis Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Amsterdam : Elsevier |
| مواضيع طبية MeSH: | Niemann-Pick Disease, Type C*/genetics , Niemann-Pick Disease, Type C*/therapy , Niemann-Pick Disease, Type C*/metabolism, Mice ; Humans ; Animals ; Cholesterol 24-Hydroxylase/metabolism ; Cholesterol 24-Hydroxylase/therapeutic use ; Cholesterol/metabolism ; Brain/metabolism ; Cerebellum/pathology |
| مستخلص: | Cholesterol 24-hydroxylase (CYP46A1) is an exclusively neuronal cytochrome P450 enzyme responsible for converting cholesterol into 24S-hydroxycholesterol, which serves as the primary pathway for eliminating cholesterol in the brain. We and others have shown that increased activity of CYP46A1 leads to reduced levels of cholesterol and has a positive effect on cognition. Therefore, we hypothesized that CYP46A1 could be a potential therapeutic target in Niemann-Pick type C (NPC) disease, a rare and fatal neurodegenerative disorder, characterized by cholesterol accumulation in endolysosomal compartments. Herein, we show that CYP46A1 ectopic expression, in cellular models of NPC and in Npc1 tm(I1061T) mice by adeno-associated virus-mediated gene therapy improved NPC disease phenotype. Amelioration in functional, biochemical, molecular and neuropathological hallmarks of NPC disease were characterized. In vivo, CYP46A1 expression partially prevented weight loss and hepatomegaly, corrected the expression levels of genes involved in cholesterol homeostasis, and promoted a redistribution of brain cholesterol accumulated in late endosomes/lysosomes. Moreover, concomitant with the amelioration of cholesterol metabolism dysregulation, CYP46A1 attenuated microgliosis and lysosomal dysfunction in mouse cerebellum, favoring a pro-resolving phenotype. In vivo CYP46A1 ectopic expression improves important features of NPC disease and may represent a valid therapeutic approach to be used concomitantly with other drugs. However, promoting cholesterol redistribution does not appear to be enough to prevent Purkinje neuronal death in the cerebellum. This indicates that cholesterol buildup in neurons might not be the main cause of neurodegeneration in this human lipidosis. Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nathalie Cartier is a founder of BrainVectis. All other authors declare not to disclose any financial interest from the present research work. (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Brain cholesterol metabolism; CYP46A1; Gene therapy; Neurodegeneration; Niemann-Pick type C disorders |
| المشرفين على المادة: | EC 1.14.14.25 (Cholesterol 24-Hydroxylase) 97C5T2UQ7J (Cholesterol) |
| تواريخ الأحداث: | Date Created: 20231224 Date Completed: 20240220 Latest Revision: 20240227 |
| رمز التحديث: | 20240227 |
| DOI: | 10.1016/j.bbadis.2023.166993 |
| PMID: | 38142760 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1879-260X |
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| DOI: | 10.1016/j.bbadis.2023.166993 |