Pathogenic Roles of Heparan Sulfate and Its Use as a Biomarker in Mucopolysaccharidoses

Abstract

Heparan sulfate (HS) is an essential glycosaminoglycan (GAG) as a component of proteoglycans, which are present on the cell surface and in the extracellular matrix. HS-containing proteoglycans not only function as structural constituents of the basal lamina but also play versatile roles in various physiological processes, including cell signaling and organ development. Thus, inherited mutations of genes associated with the biosynthesis or degradation of HS can cause various diseases, particularly those involving the bones and central nervous system (CNS). Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders involving GAG accumulation throughout the body caused by a deficiency of GAG-degrading enzymes. GAGs are stored differently in different types of MPSs. Particularly, HS deposition is observed in patients with MPS types I, II, III, and VII, all which involve progressive neuropathy with multiple CNS system symptoms. While therapies are available for certain symptoms in some types of MPSs, significant unmet medical needs remain, such as neurocognitive impairment. This review presents recent knowledge on the pathophysiological roles of HS focusing on the pathogenesis of MPSs. We also discuss the possible use and significance of HS as a biomarker for disease severity and therapeutic response in MPSs.

Enzyme replacement with transferrin receptor-targeted α-L-iduronidase rescues brain pathology in mucopolysaccharidosis I mice

“… 34 Thus, clearance of HS from the brain at early disease stage might prevent the initiation of this pathogenic cascade. 20 , 31 In fact, the removal of deposited HS by JR-171 suppressed pathological changes in the brain and further prevented the loss of spatial learning ability in the Morris water maze test. Notably, in the 31-week treatment study, neuroinflammation and neurodegeneration were already present at the baseline (11 weeks of age), indicating that the pathogenic cascade was initiated before starting the treatment.…”

“…The pathogenic roles of DS and HS may vary across organs. 30 , 31 In the brain, HS deposition in neurons and glial cells induces neuroinflammation and neurodegeneration, 32 , 33 triggering CNS manifestations and progressive deterioration of disease conditions. 34 Thus, clearance of HS from the brain at early disease stage might prevent the initiation of this pathogenic cascade.…”

Roles of the Oxytocin Receptor (OXTR) in Human Diseases

“…Depending on the kind of deficient enzyme involved in the degradation of GAGs (due to mutations in the corresponding genes) and the nature of the accumulated GAG(s), 13 types and subtypes of MPS are currently distinguished [ 116 ]. All MPS types are severe diseases, and neurodegenerative processes, accompanied with mental deficits and disorders, occur in most of them [ 114 , 116 , 117 ]. Although MPS are monogenic diseases, recent studies indicated that the expression of hundreds of genes is changed (either up- or down-regulated) in each MPS type relative to the controls [ 118 ].…”

The Interplay of Glycosaminoglycans and Cysteine Cathepsins in Mucopolysaccharidosis

“…Treatment of MPS-II mice with a blood–brain-barrier-penetrable antibody (Pabinafusp Alfa) reduces HS levels in brain and prevents neurodegeneration and neurocognitive dysfunction [ 53 ]. The accumulation of HS in MPS-I, -II, -III, and -VII affects lysosomal functions, leading to numerous irreversible alterations within and outside cells (e.g., abnormal composition of membranes, intracellular vesicle trafficking, autophagy, mitochondrial dysfunction, oxidative stress, inflammation) [ 54 , 55 ].…”