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Glial degeneration with oxidative damage drives neuronal demise in MPSII disease

Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the iduronate 2-sulfatase (IDS) enzyme, causing progressive neurodegeneration in patients. Neural stem cells (NSCs) derived from the IDS-ko mouse can recapitulate MPSII pathogenesis in vitro. In differentiati...

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Autores principales: Zalfa, Cristina, Verpelli, Chiara, D'Avanzo, Francesca, Tomanin, Rosella, Vicidomini, Cinzia, Cajola, Laura, Manara, Renzo, Sala, Carlo, Scarpa, Maurizio, Vescovi, Angelo Luigi, De Filippis, Lidia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108318/
https://www.ncbi.nlm.nih.gov/pubmed/27512952
http://dx.doi.org/10.1038/cddis.2016.231
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author Zalfa, Cristina
Verpelli, Chiara
D'Avanzo, Francesca
Tomanin, Rosella
Vicidomini, Cinzia
Cajola, Laura
Manara, Renzo
Sala, Carlo
Scarpa, Maurizio
Vescovi, Angelo Luigi
De Filippis, Lidia
author_facet Zalfa, Cristina
Verpelli, Chiara
D'Avanzo, Francesca
Tomanin, Rosella
Vicidomini, Cinzia
Cajola, Laura
Manara, Renzo
Sala, Carlo
Scarpa, Maurizio
Vescovi, Angelo Luigi
De Filippis, Lidia
author_sort Zalfa, Cristina
collection PubMed
description Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the iduronate 2-sulfatase (IDS) enzyme, causing progressive neurodegeneration in patients. Neural stem cells (NSCs) derived from the IDS-ko mouse can recapitulate MPSII pathogenesis in vitro. In differentiating IDS-ko NSCs and in the aging IDS-ko mouse brain, glial degeneration precedes neuronal degeneration. Here we show that pure IDS-ko NSC-derived astrocytes are selectively able to drive neuronal degeneration when cocultured with healthy neurons. This phenotype suggests concurrent oxidative damage with metabolic dysfunction. Similar patterns were observed in murine IDS-ko animals and in human MPSII brains. Most importantly, the mutant phenotype of IDS-ko astrocytes was reversed by low oxygen conditions and treatment with vitamin E, which also reversed the toxic effect on cocultured neurons. Moreover, at very early stages of disease we detected in vivo the development of a neuroinflammatory background that precedes astroglial degeneration, thus suggesting a novel model of MPSII pathogenesis, with neuroinflammation preceding glial degeneration, which is finally followed by neuronal death. This hypothesis is also consistent with the progression of white matter abnormalities in MPSII patients. Our study represents a novel breakthrough in the elucidation of MPSII brain pathogenesis and suggests the antioxidant molecules as potential therapeutic tools to delay MPSII onset and progression.
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spelling pubmed-51083182016-11-15 Glial degeneration with oxidative damage drives neuronal demise in MPSII disease Zalfa, Cristina Verpelli, Chiara D'Avanzo, Francesca Tomanin, Rosella Vicidomini, Cinzia Cajola, Laura Manara, Renzo Sala, Carlo Scarpa, Maurizio Vescovi, Angelo Luigi De Filippis, Lidia Cell Death Dis Original Article Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the iduronate 2-sulfatase (IDS) enzyme, causing progressive neurodegeneration in patients. Neural stem cells (NSCs) derived from the IDS-ko mouse can recapitulate MPSII pathogenesis in vitro. In differentiating IDS-ko NSCs and in the aging IDS-ko mouse brain, glial degeneration precedes neuronal degeneration. Here we show that pure IDS-ko NSC-derived astrocytes are selectively able to drive neuronal degeneration when cocultured with healthy neurons. This phenotype suggests concurrent oxidative damage with metabolic dysfunction. Similar patterns were observed in murine IDS-ko animals and in human MPSII brains. Most importantly, the mutant phenotype of IDS-ko astrocytes was reversed by low oxygen conditions and treatment with vitamin E, which also reversed the toxic effect on cocultured neurons. Moreover, at very early stages of disease we detected in vivo the development of a neuroinflammatory background that precedes astroglial degeneration, thus suggesting a novel model of MPSII pathogenesis, with neuroinflammation preceding glial degeneration, which is finally followed by neuronal death. This hypothesis is also consistent with the progression of white matter abnormalities in MPSII patients. Our study represents a novel breakthrough in the elucidation of MPSII brain pathogenesis and suggests the antioxidant molecules as potential therapeutic tools to delay MPSII onset and progression. Nature Publishing Group 2016-08 2016-08-11 /pmc/articles/PMC5108318/ /pubmed/27512952 http://dx.doi.org/10.1038/cddis.2016.231 Text en Copyright © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Zalfa, Cristina
Verpelli, Chiara
D'Avanzo, Francesca
Tomanin, Rosella
Vicidomini, Cinzia
Cajola, Laura
Manara, Renzo
Sala, Carlo
Scarpa, Maurizio
Vescovi, Angelo Luigi
De Filippis, Lidia
Glial degeneration with oxidative damage drives neuronal demise in MPSII disease
title Glial degeneration with oxidative damage drives neuronal demise in MPSII disease
title_full Glial degeneration with oxidative damage drives neuronal demise in MPSII disease
title_fullStr Glial degeneration with oxidative damage drives neuronal demise in MPSII disease
title_full_unstemmed Glial degeneration with oxidative damage drives neuronal demise in MPSII disease
title_short Glial degeneration with oxidative damage drives neuronal demise in MPSII disease
title_sort glial degeneration with oxidative damage drives neuronal demise in mpsii disease
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108318/
https://www.ncbi.nlm.nih.gov/pubmed/27512952
http://dx.doi.org/10.1038/cddis.2016.231
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