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Updated: Mar 16, 2026
Primary Cultures of Rat Astrocytes and Microglia and Their Use in the Study of Amyotrophic Lateral Sclerosis
Published on: June 23, 2022
Glial degeneration with oxidative damage drives neuronal demise in MPSII disease
Cristina Zalfa1, Chiara Verpelli2, Francesca D'Avanzo3
1Department of Biotechnology and Biosciences, University Milan Bicocca, Piazza della Scienza 2, Milano 20126, Italy.
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.
Insights
Mucopolysaccharidosis type II (MPSII) pathogenesis involves neuroinflammation preceding glial and neuronal degeneration. Antioxidants like vitamin E show promise in delaying disease progression by reversing astrocyte dysfunction.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder caused by iduronate 2-sulfatase (IDS) deficiency, leading to progressive neurodegeneration.
- Neural stem cells (NSCs) from IDS-deficient mice model MPSII pathogenesis, showing glial degeneration precedes neuronal loss in vitro and in vivo.
- This study investigates the role of astrocytes in MPSII neurodegeneration and explores potential therapeutic interventions.
Purpose of the Study:
- To elucidate the precise mechanisms of neurodegeneration in MPSII.
- To identify the role of astrocytes in the disease progression.
- To explore potential therapeutic strategies targeting oxidative stress and neuroinflammation.
Main Methods:
- Coculturing of IDS-deficient astrocytes with healthy neurons to observe neuronal degeneration.
- Analysis of oxidative damage and metabolic dysfunction in affected cells and tissues.
- In vivo studies in IDS-knockout mice and examination of human MPSII brain samples.
- Testing the efficacy of low oxygen conditions and vitamin E treatment.
Main Results:
- IDS-deficient astrocytes induce neuronal degeneration, indicating astrocyte dysfunction in MPSII.
- Oxidative damage and metabolic dysfunction are key features of the observed neurodegeneration.
- Low oxygen and vitamin E treatment reversed the detrimental effects of IDS-deficient astrocytes on neurons.
- Early-stage in vivo studies revealed a neuroinflammatory background preceding glial degeneration.
Conclusions:
- A novel model of MPSII pathogenesis is proposed: neuroinflammation precedes glial degeneration, followed by neuronal death.
- Astrocytes play a critical role in driving neurodegeneration in MPSII.
- Antioxidant molecules, such as vitamin E, represent promising therapeutic targets to mitigate MPSII progression.
