Abstract
Mucopolysaccharidoses are lysosomal storage disorders characterised by accumulation of abnormal pathological glycosaminoglycans, cellular dysfunction and widespread inflammation, resulting in progressive cognitive and motor decline. Lysosomes are important mediators of immune cell function, and therefore accumulation of glycosaminoglycans (GAGs) and other abnormal substrates could affect immune function and directly impact on disease pathogenesis. This review summarises current knowledge with regard to inflammation in mucopolysaccharidosis, with an emphasis on the brain and outlines a potential role for GAGs in induction of inflammation. We propose a model by which the accumulation of GAGs and other factors may impact on innate immune signalling with particular focus on the Toll‐like receptor 4 pathway. Innate immunity appears to have a dominating role in mucopolysaccharidosis; however, furthering understanding of innate immune signalling would have significant impact on highlighting novel anti‐inflammatory therapeutics for use in mucopolysaccharide diseases. This article is part of the Special Issue “Lysosomal Storage Disorders”.
Highlights
Pathology of MPSMPS diseases in general are characterised by increased storage of GAGs and other abnormal substrates, including but not limited to GM gangliosides, cholesterol, amyloid beta, hyperphosphorylated tau and a-synuclein
We propose a model by which the accumulation of GAGs and other factors may impact on innate immune signalling with particular focus on the Toll-like receptor 4 pathway
This review will address the role of storage materials including glycosaminoglycans, in particular heparan sulphate (HS) in the induction of Toll-like receptor 4 (TLR4) innate immune responses in MPS
Summary
MPS diseases in general are characterised by increased storage of GAGs and other abnormal substrates, including but not limited to GM gangliosides, cholesterol, amyloid beta, hyperphosphorylated tau and a-synuclein. There are probably many more that are as yet undescribed. The accumulation of these substrates has been associated with widespread inflammation, in particular CNS and joint
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