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Lysosomal and network alterations in human mucopolysaccharidosis type VII iPSC-derived neurons
Neus Bayó-Puxan1,2, Ana Paula Terrasso3,4, Sophie Creyssels1
1Institute de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France.
Abstract:
Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by deficient β-glucuronidase (β-gluc) activity. Significantly reduced β-gluc activity leads to accumulation of glycosaminoglycans (GAGs) in many tissues, including the brain. Numerous combinations of mutations in GUSB (the gene that codes for β-gluc) cause a range of neurological features that make disease prognosis and treatment challenging. Currently, there is little understanding of the molecular basis for MPS VII brain anomalies. To identify a neuronal phenotype that could be used to complement genetic analyses, we generated two iPSC clones derived from skin fibroblasts of an MPS VII patient. We found that MPS VII neurons exhibited reduced β-gluc activity and showed previously established disease-associated phenotypes, including GAGs accumulation, expanded endocytic compartments, accumulation of lipofuscin granules, more autophagosomes, and altered lysosome function. Addition of recombinant β-gluc to MPS VII neurons, which mimics enzyme replacement therapy, restored disease-associated phenotypes to levels similar to the healthy control. MPS VII neural cells cultured as 3D neurospheroids showed upregulated GFAP gene expression, which was associated with astrocyte reactivity, and downregulation of GABAergic neuron markers. Spontaneous calcium imaging analysis of MPS VII neurospheroids showed reduced neuronal activity and altered network connectivity in patient-derived neurospheroids compared to a healthy control. These results demonstrate the interplay between reduced β-gluc activity, GAG accumulation and alterations in neuronal activity, and provide a human experimental model for elucidating the bases of MPS VII-associated cognitive defects.
Insights
Mucopolysaccharidosis type VII (MPS VII) is a rare genetic disorder. This study models MPS VII neurons, revealing impaired neuronal activity and altered network connectivity, offering insights into cognitive defects.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease due to deficient beta-glucuronidase (β-gluc) activity.
- Reduced β-gluc activity causes glycosaminoglycan (GAG) accumulation, particularly in the brain, leading to complex neurological features.
- The molecular basis of MPS VII-induced brain anomalies remains poorly understood, hindering effective prognosis and treatment.
Purpose of the Study:
- To establish a human cellular model for MPS VII neurological defects using induced pluripotent stem cells (iPSCs).
- To investigate the neuronal phenotype and molecular alterations in MPS VII patient-derived neurons.
- To explore the potential of enzyme replacement therapy in correcting MPS VII-associated cellular phenotypes.
Main Methods:
- Generation of two iPSC clones from MPS VII patient skin fibroblasts.
- Culturing of MPS VII neurons and 3D neurospheroids.
- Biochemical assays for β-gluc activity and GAG levels.
- Analysis of lysosomal function, endocytic compartments, and lipofuscin accumulation.
- Gene expression analysis (GFAP, GABAergic markers).
- Spontaneous calcium imaging for neuronal activity and network connectivity assessment.
Main Results:
- MPS VII neurons exhibited reduced β-gluc activity and GAG accumulation.
- Patient-derived neurons showed lysosomal dysfunction, expanded endocytic compartments, and lipofuscin accumulation.
- Recombinant β-gluc treatment rescued these disease-associated phenotypes.
- MPS VII neurospheroids displayed astrocyte reactivity (upregulated GFAP) and reduced GABAergic neuron markers.
- Calcium imaging revealed diminished neuronal activity and altered network connectivity in MPS VII neurospheroids.
Conclusions:
- Reduced β-gluc activity and GAG accumulation in MPS VII neurons directly impact neuronal function and network connectivity.
- Patient-derived iPSC models effectively recapitulate key MPS VII neurological phenotypes.
- This study provides a valuable human experimental system for understanding MPS VII cognitive deficits and testing therapeutic strategies.
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