Abstract
BackgroundIn 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.Methodology/Principal FindingsIn 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 MIP1α 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.Conclusions/SignificanceThese 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.
Highlights
Divergent events such as deposition of Aß in Alzheimer disease [1], a-synuclein or neuromelanin in Parkinson disease [2,3], disease-associated PrPsc protein in prion disease [4], mutants SOD1 protein in amyotrophic lateral sclerosis [5], viral proteins in human immunodeficiency infection [6] or mutant huntingtin in Huntington disease [7] initiate involvement of the immune system, which in turn interacts with the nervous system and set the pace of progressive neurodegeneration
Microglial cell activation induced by HS1 or HS2 led to increased detection of TNFa, IL1ß and macrophage inflammatory protein 1a (MIP1a) mRNAs
MIP1a mRNA levels were equivalent to wild type mice. These results show that the alteration of inflammation markers in MPSIII subtype B (MPSIIIB) mice was secondary to GAG accumulation, very low residual expression in treated mice being consistent with very low residual production of heparan sulfate (HS) oligosaccharides, as expected since the therapeutic enzyme is not delivered to all brain cells [31]
Summary
Divergent events such as deposition of Aß in Alzheimer disease [1], a-synuclein or neuromelanin in Parkinson disease [2,3], disease-associated PrPsc protein in prion disease [4], mutants SOD1 protein in amyotrophic lateral sclerosis [5], viral proteins in human immunodeficiency infection [6] or mutant huntingtin in Huntington disease [7] initiate involvement of the immune system, which in turn interacts with the nervous system and set the pace of progressive neurodegeneration. Whereas the association of chronic neurodegeneration and inflammation is well established, the causative links between these events is debated. Series of evidence from studies performed in animal models of chronic neurodegeneration suggest that microglial activation might be primed by the ongoing pathology rather than the opposite. The deletions of cytokine genes have shown inconsistent, minor or no effect on disease progression in mouse models of neurodegenerative disorders [12,13]. 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
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