期刊
STEM CELL REPORTS
卷 16, 期 6, 页码 1478-1495出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2021.04.011
关键词
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资金
- Diagnosi PrePostnatale Malattie Metaboliche Laboratory (G. Gaslini Institute) [GTB07001A]
- Fondazione Telethon
- European Joint Program on Rare Diseases (EJP RD
- project NG4Leuko)
- Human Frontier Science Program (HFSP)
- European Hematology Association (EHA)
- San Raffaele Hospital
- AMED
- AIRC [23321]
- IBSA Foundation postdoctoral fellowship
- FCSR (Fondazione Centro San Raffaele) postdoctoral fellowship
- European Leukodystrophy Association [ELA 2016010I3]
- Hollis Brownstein Research Grant from Leukemia Research Foundation (LRF)
- Interstellar Initiative on Healthy Longevity from NYAS
- Hollis Brownstein Research Grant from Leukemia Research Foundation
This study investigated the impact of GALC deficiency and rescue on GLD patients' neural cells, revealing various pathological manifestations and suggesting multiple mechanisms contributing to neural pathology in GLD. It also emphasized the importance of regulated GALC expression for proper human neural commitment and differentiation.
Globoid cell leukodystrophy (GLD) is a rare neurodegenerative lysosomal storage disease caused by an inherited deficiency of B-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.
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