Mucopolysaccharidosis Types IH, IS, II and IIIA: Glycosaminoglycans and Lipids of Isolated Brain Cells and Other Fractions from Autopsied Tissues

Abstract

Brain cellular fractions were prepared in bulk from four nonneurological patients and from five patients with mucopolysaccharidosis (MPS). Glycosaminoglycans and lipids were isolated and chemically analyzed. Results of the present study: in the normal controls glycosaminoglycans as pg per mg protein (mean) were 2.2 in neuronal perikarya, 2.0 in astroglia, 2.1 in oligodendroglia, 3.3 in neuropile from gray matter, and 3.2 in a mixed fraction from white matter. In the partially myelinated axons from gray and white matter of an 8-month-old infant, the concentration was 6.9 and 2.6 pg per mg protein, compared with 2.8 and 0.8 pg per mg protein, respectively, in the adult patients. It was estimated that chondroitin sulfates constituted more than onehalf of the total glycosaminoglycan. Hyaluronic acid, heparan sulfate, and dermatan sulfate were also present in all cell types and fractions. Cholesterol, phospholipids, cerebrosides, sulfatide and gangliosides were present in all cell types and fractions, but differed widely in concentration. There was a four-to sixfold increase in the concentration of total glycosaminoglycans in the neuronal perikarya of patients with MPS IH, 11, and IIIA. The increased glycosaminoglycans were heparan sulfate in MPS IIIA, and dermatan sulfate plus heparan sulfate in MPS IH and 11. Similar changes were found in the astroglia and in the other brain fractions of those patients. The concentration of the gangliosides GMZ, GM3, GD3, and ceramide dihexoside was markedly increased in the neurons and other brain fractions of the same patients. The quantities of GM3, GMz, and GD3 together amounted to 65% of the total gangliosides of the neurons, indicating changes of the same magnitude seen in the gangliosidoses. All these patients exhibited mental retardation. The concentration and composition of glycosaminoglycans, gangliosides, and neutral hexosyl ceramides in the neuronal perikarya of the patient with MPS IS was normal. There was only a small increase of dermatan sulfate content in the neuropile, mixed fraction, and myelinated axons from the white matter and some increase of ceramide dihexoside content in the myelinated axons. This patient was an adult of normal intelligence.

CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome)

“…When MPSII mice were analyzed at 6 months of age, i.e., 4 months after administration of AAV9-Ids vectors, the content of GAGs, the general and ultrastructural aspect, and the size and function of brain lysosomes were all corrected in treated animals, but these had worsened in nontreated MPSII animals or those receiving noncoding AAV9-Null vectors. Two-month-old untreated MPSII mice also showed pronounced astrocytosis and microgliosis throughout the brain, a hallmark finding in different animal models of mucopolysaccharidoses that present with neurodegeneration (38,40,52,54,(68)(69)(70) and in Hunter syndrome patients (47,48). The effects of AAV9-mediated IDS gene transfer on the transcriptional signature and histological findings associated with microglial activation in 6-month old animals were quite striking and were in agreement with our previous observations in MPSIIIB mice (40).…”

“…Moreover, the expression of genes assigned to microglia by CTEN was clearly normalized following treatment with AAV-Ids ( Figure 6C). These results are in agreement with our previous observations in MPSIIIB mice (40) and support the established notion that microglia plays a key role in CNS pathology in all forms of MPS (47,48,53,56,57). Moreover, our results demonstrate the efficacy of intra-CSF delivery of AAV9-Ids in eradicating neuroinflammation.…”

“…In most cases, enzymatic activities were significantly altered; while HGSNAT and β-HEXO showed increased activity, the activities of SGSH and GALNS were reduced (Supplemental Figure 1D). MPSII, like many other LSD with CNS involvement, is characterized by the presence of neuroinflammation, defined by chronic activation of glial cells (47,48). Immunostaining for glial fibrillary acidic protein (GFAP), a protein upregulated upon astrocytic activation (49), and staining with Bandeiraea simplicifolia isolectin B4 (BSI-B4) lectin, which labels microglia (50), revealed the presence of astrocytosis (Supplemental Figure 2A) and microgliosis (Supplemental Figure 2B) in the encephalon of 2-month-old MPSII mice.…”

Functional abnormalities of heparan sulfate in mucopolysaccharidosis-I are associated with defective biologic activity of FGF-2 on human multipotent progenitor cells

“…[16][17][18]33,[38][39][40] Overall, our findings are consistent with these studies. A unique aspect of our study is that we examined metabolically radiolabeled GAGs obtained from the progeny of primary, multipotent stem-cell populations from the BM of patients with Hurler syndrome and healthy volunteers.…”

Neurobiology and cellular pathogenesis of glycolipid storage diseases

“…(c) GM2 ganglioside storage in mucopolysaccharidoses is linked to cholesterol accumulation and ectopic dendritogenesis Abnormal accumulation of GM2 and GM3 gangliosides has also been found to occur in several types of MPS storage disease (Constantopoulos et al 1980) and as described in § 3a, the abnormal elevation of GM2 correlates with the presence of ectopic dendritogenesis in feline MPS type I (Walkley et al 1988b) and MPS VI (S. U. Walkley, M. E. Haskins and M. A. Thrall, unpublished data) diseases. Neurons in MPS diseases accumulate specific types of GAG secondary to defects in specific lysosomal hydrolases, but as suggested by accompanying ganglioside accumulation, the storage process is complex.…”