Abstract
Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the iduronate 2-sulfatase (IDS) enzyme, causing progressive neurodegeneration in patients. Neural stem cells (NSCs) derived from the IDS-ko mouse can recapitulate MPSII pathogenesis in vitro. In differentiating IDS-ko NSCs and in the aging IDS-ko mouse brain, glial degeneration precedes neuronal degeneration. Here we show that pure IDS-ko NSC-derived astrocytes are selectively able to drive neuronal degeneration when cocultured with healthy neurons. This phenotype suggests concurrent oxidative damage with metabolic dysfunction. Similar patterns were observed in murine IDS-ko animals and in human MPSII brains. Most importantly, the mutant phenotype of IDS-ko astrocytes was reversed by low oxygen conditions and treatment with vitamin E, which also reversed the toxic effect on cocultured neurons. Moreover, at very early stages of disease we detected in vivo the development of a neuroinflammatory background that precedes astroglial degeneration, thus suggesting a novel model of MPSII pathogenesis, with neuroinflammation preceding glial degeneration, which is finally followed by neuronal death. This hypothesis is also consistent with the progression of white matter abnormalities in MPSII patients. Our study represents a novel breakthrough in the elucidation of MPSII brain pathogenesis and suggests the antioxidant molecules as potential therapeutic tools to delay MPSII onset and progression.
Highlights
Mucopolysaccharidosis type II (MPSII, Hunter Syndrome, MIM: 309900) is caused by mutations in the gene encoding the lysosomal enzyme iduronate 2-sulfatase (IDS), with resulting accumulation of the glycosaminoglycans (GAGs), heparan and dermatan sulfate in the lysosomes
We previously showed that glial degeneration precedes neuronal demise both in vivo, in the MPSII mouse brain, and in vitro, in neural stem cells (NSCs) derived from the subventricular zone (SVZ) of adult IDS-ko mouse brain.[2]
Our observation of human Hunter fibroblasts stained with MitoTracker and JC1 (Figure 1f) showed mitochondria spread in more fragmented structures and with a significantly shorter mitochondrial chain length compared with controls (Figure 1g), consistent with what observed in other lysosomal storage diseases (LSDs).[11,12]
Summary
Mucopolysaccharidosis type II (MPSII, Hunter Syndrome, MIM: 309900) is caused by mutations in the gene encoding the lysosomal enzyme iduronate 2-sulfatase (IDS), with resulting accumulation of the glycosaminoglycans (GAGs), heparan and dermatan sulfate in the lysosomes. We recently showed that neural stem cells (NSCs) derived from the subventricular zone (SVZ) of the IDS-ko mouse, the animal model of MPSII, mimic brain pathogenesis in vitro. Our work shows that microgliosis/astrogliosis, along with an increase of oxidative damage-related hallmarks, coincide with GAG accumulation as very early events in MPSII pathogenesis and precede glial degeneration, which leads to neuronal death. In this scenario, the exploitation of antioxidants and neurotrophins[2] or the transplantation of NSC-derived glial progenitors combined with ERT may be considered for MPSII treatment
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