Differential distribution of heparan sulfate glycoforms and elevated expression of heparan sulfate biosynthetic enzyme genes in the brain of mucopolysaccharidosis IIIB mice

Abstract

The primary pathology in mucopolysaccharidosis (MPS) IIIB is lysosomal storage of heparan sulfate (HS) glycosaminoglycans, leading to complex neuropathology and dysfunction, for which the detailed mechanisms remain unclear. Using antibodies that recognize specific HS glycoforms, we demonstrate differential cell-specific and domain-specific lysosomal HS-GAG distribution in MPS IIIB mouse brain. We also describe a novel neuron-specific brain HS epitope with broad, non-specific increase in the expression in all neurons in MPS IIIB mouse brain, including cerebellar granule neurons, which do not exhibit lysosomal storage pathology. This suggests that biosynthesis of certain HS glycoforms is enhanced throughout the CNS of MPS IIIB mice. Such a conclusion is further supported by demonstration of increased expression of multiple genes encoding enzymes essential in HS biosynthesis, including HS sulfotransferases and epimerases, as well as FGFs, for which HS serves as a co-receptor, in MPS IIIB brain. These data suggest that lysosomal storage of HS may lead to the increase in HS biosyntheses, which may contribute to the neuropathology of MPS IIIB by exacerbating the lysosomal HS storage.

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…In MPSs, the lysosomal accumulation of undigested GAGs is considered the "primum movens" of the subsequent functional cell impairment; however, evidence demonstrates that the accumulation of storage material does not occur only in the lysosomes, but also on the cell surface and ECM where GAGs form proteoglycans through their covalent binding to a core protein [105,106,109]. The accumulation of storage material in non-lysosomal compartments accounts for impaired cell signaling and trafficking, protein unfolding, abnormal autophagy, alterations of intracellular calcium homeostasis, lysolipid accumulation, and modifications in other cellular processes that ultimately lead to the MPS phenotypes [150][151][152][153][154][155][156][157][158][159].…”

Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

“…1,3 While detailed mechanisms of pathology, especially the neuropathology of MPS III, are not yet well understood, numerous studies have reported cascades of complex secondary pathological events in the CNS, including broad metabolic impairments, [4][5][6] neuroinflammation, 5,7-11 oxidative stress, 10,12 autophagy, 13,14 and neurodegeneration. 7,9,11,[15][16][17][18][19][20] It is worth noting that many of these secondary neuropathological features of MPS IIIB, such as b-amyloid (Ab) aggregation, 15,18 tauopathy, 17,18 synucleinopathy, 16,19 oxidative stress, 10,12 and neuroimflammation, 5,[7][8][9][10][11] are also common hallmarks of other neurodegenerative diseases like Alzheimer's (AD) 21,22 and Parkinson's disease (PD). 23,24 In addition, our recent studies demonstrate widespread profound neuropathology in the peripheral nervous system (PNS), 25 indicating that neuropathological manifestation affects the entire nervous system.…”

Peripheral Nervous System Neuropathology and Progressive Sensory Impairments in a Mouse Model of Mucopolysaccharidosis IIIB

“…Further, it is commonly accepted that in the brain, multiple factors contribute to the neuropathology, secondary to the primary pathology- the lysosomal storage of HS-GAGs [4], [6], [7], [8], [9], [10], [11], [12], [13], [14]. The complex MPS IIIB neuropathology has been shown to involve impaired metabolism, inflammation, neurodegeneration, reactive oxygen species and tauopathy.…”

“…It is known that the lysosomal storage pathology of MPS IIIB is global throughout the CNS and neuropathology studies have focused predominantly on changes in the brain, though previous studies showed lysosomal storage lesions in all parts of the CNS in mice and dogs [4] , [5] . Further, it is commonly accepted that in the brain, multiple factors contribute to the neuropathology, secondary to the primary pathology- the lysosomal storage of HS-GAGs [4] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] . The complex MPS IIIB neuropathology has been shown to involve impaired metabolism, inflammation, neurodegeneration, reactive oxygen species and tauopathy.…”