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

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.

Involvement of the Toll-like receptor 4 pathway and use of TNF-α antagonists for treatment of the mucopolysaccharidoses

“…This concept was recently supported by the findings of Ausseil et al (6), who demonstrated priming of microglia via the TLR4 pathway in the brains of MPS IIIB mice. In addition to heparan sulfate fragments, gangliosides accumulate in the brains of MPS IIIB mice, and it is possible that gangliosides and/or other storage products in connective tissue cells may also contribute to TLR4 activation.…”

“…3F). TNF-α is an important downstream mediator of TLR4, and several investigators have recently shown that TLR4 activation and/or TNF-α has important pathogenic effects in the brains of MPS mouse models (6,25). We therefore examined the locomotor behavior of the DKO mice using an accelerating rotarod (Fig.…”

Storage Vesicles in Neurons Are Related to Golgi Complex Alterations in Mucopolysaccharidosis IIIB

“…The associated accumulation of substances like GM3 gangliosides, 21 subunit c of mitochondrial ATP synthase (ScMAS), 22 ubiquitin, or lysozyme 23 is not currently understood. Mechanisms leading to the development of neuroinflammation 24 and loss of synaptophysin expression, 25 which both predominates in the rostral cortex, and neuropathology, which is spread throughout the central nervous system, are also ignored. Neurological manifestations are predominant in children with MPSIIIB, evolving over few years from behavioral changes to profound mental retardation.…”

Cell-and Gene-based Therapeutic Approaches for Neurological Deficits in Mucopolysaccharidoses

“…The role of toll-like receptors (TLR) signaling has been highlighted as one of the major contributors to brain inflammatory responses and microglial cell activation with age and neurodegenerative diseases [31]. Recent findings by Ausseil et al have demonstrated that microglial cell activation could be primed by heparan sulfate oligosaccharides via the TLR4 pathway in the brains of MPS IIIB mice at very early stage of the disease [32]. In addition, it has been reported that changes in ganglioside expression or availability at the plasmalemma may also alter TLR4 signaling pathway and trigger microglial activation [33].…”