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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.

SUBMITTER: Mangiameli E

PROVIDER: S-EPMC8190599 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Mangiameli Elisabeth E Cecchele Anna A Morena Francesco F Sanvito Francesca F Matafora Vittoria V Cattaneo Angela A Della Volpe Lucrezia L Gnani Daniela D Paulis Marianna M Susani Lucia L Martino Sabata S Di Micco Raffaella R Bachi Angela A Gritti Angela A

Stem cell reports 20210513 6

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 pro ...[more]

PMID: 33989519

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Project description:IntroductionMitochondrial dysfunction is observed in Alzheimer's disease (AD). Altered mitochondrial respiration, cytochrome oxidase (COX) Vmax, and mitophagy are observed in human subjects and animal models of AD. Models derived from induced pluripotent stem cells (iPSCs) may not recapitulate these phenotypes after reprogramming from differentiated adult cells.MethodsWe examined mitochondrial function across iPSC derived models including cerebral organoids, forebrain neurons, and astrocytes. iPSCs were reprogrammed from fibroblasts either from the University of Kansas Alzheimer's Disease Research Center (KU ADRC) cohort or purchased from WiCell. A total of four non-demented and four sporadic AD iPSC lines were examined. Models were subjected to mitochondrial respiration analysis using Seahorse XF technology, spectrophotometric cytochrome oxidase (COX) Vmax assays, fluorescent assays to determine mitochondrial mass, mitochondrial membrane potential, calcium, mitochondrial dynamics, and mitophagy levels. AD pathological hallmarks were also measured.ResultsiPSC derived neurons and cerebral organoids showed reduced COX Vmax in AD subjects with more profound defects in the female cohort. These results were not observed in astrocytes. iPSC derived neurons and astrocytes from AD subjects had reduced mitochondrial respiration parameters with increased glycolytic flux. iPSC derived neurons and astrocytes from AD subjects showed sex dependent effects on mitochondrial membrane potential, mitochondrial superoxide production, and mitochondrial calcium. iPSC derived neurons from AD subjects had reduced mitochondrial localization in lysosomes with sex dependent effects on mitochondrial mass, while iPSC derived astrocytes from female AD subjects had increased mitochondrial localization to lysosomes. Both iPSC derived neurons and astrocytes from AD subjects showed altered mitochondrial dynamics. iPSC derived neurons had increased secreted Aβ, and sex dependent effects on total APP protein expression. iPSC derived astrocytes showed sex dependent changes in GFAP expression in AD derived cells.ConclusionOverall, iPSC derived models from AD subjects show mitochondrial phenotypes and AD pathological hallmarks in a cell type and sex dependent manner. These results highlight the importance of sex as a biological variable in cell culture studies.

Dataset Information

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

Publications

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

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