Early Neurodegeneration Progresses Independently of Microglial Activation by Heparan Sulfate in the Brain of Mucopolysaccharidosis IIIB Mice

• DOI: 10.1371/journal.pone.0002296
• Publication Date: 2008-05-28T02:51:42Z
• Authors: 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
• Keywords: 0303 health sciences; Base Sequence; Science; Q; R; Gene Transfer Techniques; Brain; Fluorescent Antibody Technique; Enzyme-Linked Immunosorbent Assay; Mice, Mutant Strains; Mice; Mucopolysaccharidosis III; 03 medical and health sciences; Medicine; Animals; Humans; Heparitin Sulfate; Microglia; Child; Research Article; DNA Primers

BackgroundIn mucopolysaccharidosis type IIIB, a lysosomal storage disease causing early onset mental retardation in children, the production of abnormal oligosaccharidic fragments heparan sulfate is associated with severe neuropathology and chronic brain inflammation. We addressed causative links between biochemical, pathological inflammatory disorders mouse model this disease.Methodology/Principal FindingsIn cell culture, oligosaccharides activated microglial cells by signaling through Toll-like receptor 4 adaptor protein MyD88. CD11b positive three-fold increased expression mRNAs coding for chemokine MIP1α were observed at 10 days cortex MPSIIIB mice, but not mice deleted or MyD88, indicating priming brain. Whereas inflammation was delayed several months doubly mutant versus markers unchanged, similar progression neurodegenerative process absence oligosaccharides. In contrast to younger aged affected TLR4/MyD88 deficiency.Conclusions/SignificanceThese results indicate microglia HS pathway. Although intrinsic disease, phenomenon major determinant process. Inflammation may still contribute neurodegeneration late stages albeit independent TLR4/MyD88. The support view that primarily autonomous pediatric disease.