Abstract
Recent studies on developing three-dimensional (3D) brain organoids from stem cells have allowed the generation of in vitro models of neural disease and have enabled the screening of drugs because these organoids mimic the complexity of neural tissue. Niemann-Pick disease, type C (NPC) is a neurodegenerative lysosomal storage disorder caused by mutations in the NPC1 or NPC2. The pathological features underlying NPC are characterized by the abnormal accumulation of cholesterol in acidic compartments, including late endosomes and lysosomes. Due to the inaccessibility of brain tissues from human NPC patients, we developed NPC brain organoids with induced neural stem cells from NPC patient-derived fibroblasts. NPC organoids exhibit significantly reduced size and proliferative ability, which are accompanied by accumulation of cholesterol, impairment in neuronal differentiation, and autophagic flux and dysfunction of lysosomes; therefore, NPC organoids can recapitulate the main phenotypes of NPC patients. Furthermore, these pathological phenotypes observed in NPC organoids were reversed by treatment with valproic acid and HPBCD, which are known to be an effective treatment for several neurodegenerative diseases. Our data present patient-specific phenotypes in 3D organoid-based models of NPC and highlight the application of this model to drug screening in vitro.
Highlights
IntroductionIntroduction NiemannPick disease type C (NPC) is the rare neurodegenerative disease caused by mutations of NPC1 (~95%) and NPC2 (~5%) that lead to the progressive neurodegeneration of the central nervous system
1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction Niemann–Pick disease type C (NPC) is the rare neurodegenerative disease caused by mutations of NPC1 (~95%) and NPC2 (~5%) that lead to the progressive neurodegeneration of the central nervous system
Modeling NPC disease with induced neural stem cells (iNSCs) in two-dimensional (2D) cell culture recapitulates the pathological characteristics of the disease, the analysis of the pathophysiology associated with the neuronal damage in the brain has been challenging due to the limited availability of human brain tissue
Summary
Introduction NiemannPick disease type C (NPC) is the rare neurodegenerative disease caused by mutations of NPC1 (~95%) and NPC2 (~5%) that lead to the progressive neurodegeneration of the central nervous system. NPC patients exhibit progressive neurodegeneration including Purkinje cell death associated with motor impairment, problems. NPC disease, we applied an in vitro model system using induced neural stem cells (iNSCs). Lee et al Cell Death and Disease (2020)11:1059 optimized the generation of iNSCs from various human cell sources, including blood cells, mesenchymal stem cells, and fibroblasts[11,12,13,14]. We investigated NPC disease with disease-specific iNSCs from patient-derived fibroblasts using two reprogramming factors, SOX2 and HMGA2 Modeling NPC disease with iNSCs in two-dimensional (2D) cell culture recapitulates the pathological characteristics of the disease, the analysis of the pathophysiology associated with the neuronal damage in the brain has been challenging due to the limited availability of human brain tissue. Modeling the human brain is inevitable for the investigation of NPC disorders
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