Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes
| Autor: | Angela Bachi, Elisabeth Mangiameli, Vittoria Matafora, Angela Pesenti Gritti, Lucrezia della Volpe, Lucia Susani, Daniela Gnani, Marianna Paulis, Francesca Sanvito, Sabata Martino, Anna Cecchele, Raffaella Di Micco, Francesco Morena, Angela Cattaneo |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Senescence leukodystrophy senescence Genetic enhancement lysosomal enzymes Induced Pluripotent Stem Cells oligodendrocytes neurons neural progenitors Biology Biochemistry Article 03 medical and health sciences 0302 clinical medicine Pluripotent stem cells Genetics Lysosomal storage disease medicine Humans Genetic Predisposition to Disease Progenitor cell Induced pluripotent stem cell Cells Cultured Stem Cells Neurodegeneration Leukodystrophy Psychosine Cell Differentiation Cell Biology Genetic Therapy medicine.disease Phenotype gene therapy Cell biology Leukodystrophy Globoid Cell Oligodendroglia 030104 developmental biology GALC activity Krabbe disease 030217 neurology & neurosurgery Developmental Biology Galactosylceramidase |
| Zdroj: | Stem Cell Reports |
| ISSN: | 2213-6711 |
| Popis: | Summary Globoid cell leukodystrophy (GLD) is a rare neurodegenerative lysosomal storage disease caused by an inherited deficiency of β-galactocerebrosidase (GALC). GLD pathogenesis and therapeutic correction have been poorly studied in patient neural cells. Here, we investigated the impact of GALC deficiency and lentiviral vector-mediated GALC rescue/overexpression in induced pluripotent stem cell (iPSC)-derived neural progenitors and neuronal/glial progeny obtained from two GLD patients. GLD neural progeny displayed progressive psychosine storage, oligodendroglial and neuronal defects, unbalanced lipid composition, and early activation of cellular senescence, depending on the disease-causing mutation. The partial rescue of the neural differentiation program upon GALC reconstitution and psychosine clearance suggests multiple mechanisms contributing to neural pathology in GLD. Also, the pathological phenotype associated to supraphysiological GALC levels highlights the need of regulated GALC expression for proper human neural commitment/differentiation. These data have important implications for establishing safe therapeutic strategies to enhance disease correction of GLD. Highlights • GLD hiPSC-derived neural progenitors show defective neuronal/glial differentiation • GLD neural progeny displays psychosine storage and modest lysosomal impairment • Lipidome unbalance and cellular senescence contribute to the GLD phenotype • Restoring GALC activity partially rescues the GLD phenotypic defects In this article, Mangiameli et al. study the impact of GALC deficiency and lentiviral vector-mediated GALC rescue/overexpression in GLD hiPSC-derived neural progenitors and their neuronal/glial progeny. The study uncovers unforeseen mutation- and cell type-specific early pathogenic events (i.e. lipid unbalance and activation of a senescence program) that may contribute to GLD neuropathology along with psychosine storage, with important therapeutic implications. |
| Databáze: | OpenAIRE |
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