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Adenosine A(2A) receptor stimulation restores cell functions and differentiation in Niemann-Pick type C-like oligodendrocytes

Niemann Pick type C (NPC) disease is a rare neurovisceral disorder. Mutations in npc1 gene induce an intracellular accumulation of unesterified cholesterol in the endosomal/lysosomal system causing cell death. We recently showed that stimulation of adenosine A(2A) receptors (A(2A)R) restores cholest...

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Autores principales: De Nuccio, Chiara, Bernardo, Antonietta, Ferrante, Antonella, Pepponi, Rita, Martire, Alberto, Falchi, Mario, Visentin, Sergio, Popoli, Patrizia, Minghetti, Luisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611770/
https://www.ncbi.nlm.nih.gov/pubmed/31278313
http://dx.doi.org/10.1038/s41598-019-46268-8
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author De Nuccio, Chiara
Bernardo, Antonietta
Ferrante, Antonella
Pepponi, Rita
Martire, Alberto
Falchi, Mario
Visentin, Sergio
Popoli, Patrizia
Minghetti, Luisa
author_facet De Nuccio, Chiara
Bernardo, Antonietta
Ferrante, Antonella
Pepponi, Rita
Martire, Alberto
Falchi, Mario
Visentin, Sergio
Popoli, Patrizia
Minghetti, Luisa
author_sort De Nuccio, Chiara
collection PubMed
description Niemann Pick type C (NPC) disease is a rare neurovisceral disorder. Mutations in npc1 gene induce an intracellular accumulation of unesterified cholesterol in the endosomal/lysosomal system causing cell death. We recently showed that stimulation of adenosine A(2A) receptors (A(2A)R) restores cholesterol accumulation in late endosomes/lysosomes in human NPC fibroblasts and neural cell lines transiently transfected with NPC1 siRNA, suggesting that these receptors might be targeted to contrast the disease. Since NPC1 disease is characterized by dysmyelination and maturational arrest of oligodendrocyte progenitors (OPs), in this study, we investigated whether A(2A)R stimulation could promote oligodendrocyte differentiation and myelin formation, thus overcoming these important neurological abnormalities. We developed a NPC1 pharmacological model, in which primary cultures of OPs are exposed to a cholesterol transport inhibitor to induce a NPC1-like phenotype characterized by several typical features such as (i) cholesterol accumulation, (ii) altered mitochondrial morphology and membrane potential, (iii) defect of autophagy and (iv) maturation arrest. The A(2A)R agonist CGS21680 normalized all NPC1-like features. The ability of CGS21680 of rescuing OP from maturational arrest and promoting their differentiation to mature OL, suggests that A(2A)R stimulation might be exploited to correct dysmyelination in NPC1, further supporting their therapeutic potential in the disease.
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spelling pubmed-66117702019-07-15 Adenosine A(2A) receptor stimulation restores cell functions and differentiation in Niemann-Pick type C-like oligodendrocytes De Nuccio, Chiara Bernardo, Antonietta Ferrante, Antonella Pepponi, Rita Martire, Alberto Falchi, Mario Visentin, Sergio Popoli, Patrizia Minghetti, Luisa Sci Rep Article Niemann Pick type C (NPC) disease is a rare neurovisceral disorder. Mutations in npc1 gene induce an intracellular accumulation of unesterified cholesterol in the endosomal/lysosomal system causing cell death. We recently showed that stimulation of adenosine A(2A) receptors (A(2A)R) restores cholesterol accumulation in late endosomes/lysosomes in human NPC fibroblasts and neural cell lines transiently transfected with NPC1 siRNA, suggesting that these receptors might be targeted to contrast the disease. Since NPC1 disease is characterized by dysmyelination and maturational arrest of oligodendrocyte progenitors (OPs), in this study, we investigated whether A(2A)R stimulation could promote oligodendrocyte differentiation and myelin formation, thus overcoming these important neurological abnormalities. We developed a NPC1 pharmacological model, in which primary cultures of OPs are exposed to a cholesterol transport inhibitor to induce a NPC1-like phenotype characterized by several typical features such as (i) cholesterol accumulation, (ii) altered mitochondrial morphology and membrane potential, (iii) defect of autophagy and (iv) maturation arrest. The A(2A)R agonist CGS21680 normalized all NPC1-like features. The ability of CGS21680 of rescuing OP from maturational arrest and promoting their differentiation to mature OL, suggests that A(2A)R stimulation might be exploited to correct dysmyelination in NPC1, further supporting their therapeutic potential in the disease. Nature Publishing Group UK 2019-07-05 /pmc/articles/PMC6611770/ /pubmed/31278313 http://dx.doi.org/10.1038/s41598-019-46268-8 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
De Nuccio, Chiara
Bernardo, Antonietta
Ferrante, Antonella
Pepponi, Rita
Martire, Alberto
Falchi, Mario
Visentin, Sergio
Popoli, Patrizia
Minghetti, Luisa
Adenosine A(2A) receptor stimulation restores cell functions and differentiation in Niemann-Pick type C-like oligodendrocytes
title Adenosine A(2A) receptor stimulation restores cell functions and differentiation in Niemann-Pick type C-like oligodendrocytes
title_full Adenosine A(2A) receptor stimulation restores cell functions and differentiation in Niemann-Pick type C-like oligodendrocytes
title_fullStr Adenosine A(2A) receptor stimulation restores cell functions and differentiation in Niemann-Pick type C-like oligodendrocytes
title_full_unstemmed Adenosine A(2A) receptor stimulation restores cell functions and differentiation in Niemann-Pick type C-like oligodendrocytes
title_short Adenosine A(2A) receptor stimulation restores cell functions and differentiation in Niemann-Pick type C-like oligodendrocytes
title_sort adenosine a(2a) receptor stimulation restores cell functions and differentiation in niemann-pick type c-like oligodendrocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611770/
https://www.ncbi.nlm.nih.gov/pubmed/31278313
http://dx.doi.org/10.1038/s41598-019-46268-8
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