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Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes.

Abstract
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.
AuthorsElisabeth Mangiameli, Anna Cecchele, Francesco Morena, Francesca Sanvito, Vittoria Matafora, Angela Cattaneo, Lucrezia Della Volpe, Daniela Gnani, Marianna Paulis, Lucia Susani, Sabata Martino, Raffaella Di Micco, Angela Bachi, Angela Gritti
JournalStem cell reports (Stem Cell Reports) Vol. 16 Issue 6 Pg. 1478-1495 (06 08 2021) ISSN: 2213-6711 [Electronic] United States
PMID33989519 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Psychosine
  • Galactosylceramidase
Topics
  • Cell Differentiation
  • Cells, Cultured
  • Galactosylceramidase (genetics, metabolism)
  • Genetic Predisposition to Disease
  • Genetic Therapy (methods)
  • Humans
  • Induced Pluripotent Stem Cells (metabolism)
  • Leukodystrophy, Globoid Cell (genetics, metabolism)
  • Oligodendroglia (metabolism)
  • Phenotype
  • Psychosine (metabolism)
  • Stem Cells (metabolism)

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