Lysosomal and network alterations in human mucopolysaccharidosis type VII iPSC-derived neurons.

摘要: 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 mutations GUSB (the gene that codes for β-gluc) cause range neurological features make prognosis and treatment challenging. Currently, there little understanding molecular basis MPS brain anomalies. To identify neuronal phenotype could be used complement genetic analyses, we generated two iPSC clones derived from skin fibroblasts an patient. We found neurons exhibited showed previously established disease-associated phenotypes, GAGs accumulation, expanded endocytic compartments, lipofuscin granules, more autophagosomes, altered lysosome function. Addition recombinant neurons, which mimics enzyme replacement therapy, restored phenotypes levels similar healthy control. neural cells cultured as 3D neurospheroids upregulated GFAP expression, was associated with astrocyte reactivity, downregulation GABAergic neuron markers. Spontaneous calcium imaging analysis network connectivity patient-derived compared These results demonstrate interplay between activity, GAG alterations provide human experimental model elucidating bases VII-associated cognitive defects.