Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice.

<h4>Background</h4>In mucopolysaccharidosis type IIIB, a lysosomal storage disease causing early onset mental retardation in children, the production of abnormal oligosaccharidic fragments of heparan sulfate is associated with severe neuropathology and chronic brain inflammation. We addr...

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Autores principales: Jérôme Ausseil, Nathalie Desmaris, Stéphanie Bigou, Ruben Attali, Sébastien Corbineau, Sandrine Vitry, Mathieu Parent, David Cheillan, Maria Fuller, Irène Maire, Marie-Thérèse Vanier, Jean-Michel Heard
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Publicado: Public Library of Science (PLoS) 2008
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spelling oai:doaj.org-article:d00cced0622248f8a8442294492409c52021-11-25T06:12:17ZEarly neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice.1932-620310.1371/journal.pone.0002296https://doaj.org/article/d00cced0622248f8a8442294492409c52008-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18509511/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>In mucopolysaccharidosis type IIIB, a lysosomal storage disease causing early onset mental retardation in children, the production of abnormal oligosaccharidic fragments of heparan sulfate is associated with severe neuropathology and chronic brain inflammation. We addressed causative links between the biochemical, pathological and inflammatory disorders in a mouse model of this disease.<h4>Methodology/principal findings</h4>In cell culture, heparan sulfate oligosaccharides activated microglial cells by signaling through the Toll-like receptor 4 and the adaptor protein MyD88. CD11b positive microglial cells and three-fold increased expression of mRNAs coding for the chemokine MIP1alpha were observed at 10 days in the brain cortex of MPSIIIB mice, but not in MPSIIIB mice deleted for the expression of Toll-like receptor 4 or the adaptor protein MyD88, indicating early priming of microglial cells by heparan sulfate oligosaccharides in the MPSIIIB mouse brain. Whereas the onset of brain inflammation was delayed for several months in doubly mutant versus MPSIIIB mice, the onset of disease markers expression was unchanged, indicating similar progression of the neurodegenerative process in the absence of microglial cell priming by heparan sulfate oligosaccharides. In contrast to younger mice, inflammation in aged MPSIIIB mice was not affected by TLR4/MyD88 deficiency.<h4>Conclusions/significance</h4>These results indicate priming of microglia by HS oligosaccharides through the TLR4/MyD88 pathway. Although intrinsic to the disease, this phenomenon is not a major determinant of the neurodegenerative process. Inflammation may still contribute to neurodegeneration in late stages of the disease, albeit independent of TLR4/MyD88. The results support the view that neurodegeneration is primarily cell autonomous in this pediatric disease.Jérôme AusseilNathalie DesmarisStéphanie BigouRuben AttaliSébastien CorbineauSandrine VitryMathieu ParentDavid CheillanMaria FullerIrène MaireMarie-Thérèse VanierJean-Michel HeardPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 5, p e2296 (2008)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Jérôme Ausseil
Nathalie Desmaris
Stéphanie Bigou
Ruben Attali
Sébastien Corbineau
Sandrine Vitry
Mathieu Parent
David Cheillan
Maria Fuller
Irène Maire
Marie-Thérèse Vanier
Jean-Michel Heard
Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice.
description <h4>Background</h4>In mucopolysaccharidosis type IIIB, a lysosomal storage disease causing early onset mental retardation in children, the production of abnormal oligosaccharidic fragments of heparan sulfate is associated with severe neuropathology and chronic brain inflammation. We addressed causative links between the biochemical, pathological and inflammatory disorders in a mouse model of this disease.<h4>Methodology/principal findings</h4>In cell culture, heparan sulfate oligosaccharides activated microglial cells by signaling through the Toll-like receptor 4 and the adaptor protein MyD88. CD11b positive microglial cells and three-fold increased expression of mRNAs coding for the chemokine MIP1alpha were observed at 10 days in the brain cortex of MPSIIIB mice, but not in MPSIIIB mice deleted for the expression of Toll-like receptor 4 or the adaptor protein MyD88, indicating early priming of microglial cells by heparan sulfate oligosaccharides in the MPSIIIB mouse brain. Whereas the onset of brain inflammation was delayed for several months in doubly mutant versus MPSIIIB mice, the onset of disease markers expression was unchanged, indicating similar progression of the neurodegenerative process in the absence of microglial cell priming by heparan sulfate oligosaccharides. In contrast to younger mice, inflammation in aged MPSIIIB mice was not affected by TLR4/MyD88 deficiency.<h4>Conclusions/significance</h4>These results indicate priming of microglia by HS oligosaccharides through the TLR4/MyD88 pathway. Although intrinsic to the disease, this phenomenon is not a major determinant of the neurodegenerative process. Inflammation may still contribute to neurodegeneration in late stages of the disease, albeit independent of TLR4/MyD88. The results support the view that neurodegeneration is primarily cell autonomous in this pediatric disease.
format article
author Jérôme Ausseil
Nathalie Desmaris
Stéphanie Bigou
Ruben Attali
Sébastien Corbineau
Sandrine Vitry
Mathieu Parent
David Cheillan
Maria Fuller
Irène Maire
Marie-Thérèse Vanier
Jean-Michel Heard
author_facet Jérôme Ausseil
Nathalie Desmaris
Stéphanie Bigou
Ruben Attali
Sébastien Corbineau
Sandrine Vitry
Mathieu Parent
David Cheillan
Maria Fuller
Irène Maire
Marie-Thérèse Vanier
Jean-Michel Heard
author_sort Jérôme Ausseil
title Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice.
title_short Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice.
title_full Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice.
title_fullStr Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice.
title_full_unstemmed Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice.
title_sort early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis iiib mice.
publisher Public Library of Science (PLoS)
publishDate 2008
url https://doaj.org/article/d00cced0622248f8a8442294492409c5
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