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Abstract
Niemann-Pick disease type C (NPC) is a neurodegenerative and lysosomal lipid storage disorder, characterized by the abnormal accumulation of unesterified cholesterol and glycolipids, which is caused by mutations in the NPC1 genes. Here, we report the generation of human induced neural stem cells from NPC patient-derived fibroblasts (NPC-iNSCs) using only two reprogramming factors SOX2 and HMGA2 without going through the pluripotent state. NPC-iNSCs were stably expandable and differentiated into neurons, astrocytes, and oligodendrocytes. However, NPC-iNSCs displayed defects in self-renewal and neuronal differentiation accompanied by cholesterol accumulation, suggesting that NPC-iNSCs retain the main features of NPC. This study revealed that the cholesterol accumulation and the impairments in self-renewal and neuronal differentiation in NPC-iNSCs were significantly improved by valproic acid. Additionally, we demonstrated that the inhibition of cholesterol transportation by U18666A in WT-iNSCs mimicked the impaired self-renewal and neuronal differentiation of NPC-iNSCs, indicating that the regulation of cholesterol homeostasis is a crucial determinant for the neurodegenerative features of NPC. Taken together, these findings suggest that NPC-iNSCs can serve as an unlimited source of neural cells for pathological study or drug screening in a patient specific manner. Furthermore, this direct conversion technology might be extensively applicable for other human neurodegenerative diseases.
Highlights
Niemann-Pick disease type C (NPC) is an autosomal recessive and neurodegenerative disease caused by mutations in either the NPC1 (95% of cases) or the NPC2 gene (5% of cases) [1]
This study revealed that the cholesterol accumulation and the impairments in self-renewal and neuronal differentiation in NPC-induced neural stem cells (iNSCs) were significantly improved by valproic acid
Following valproic acid (VPA) treatment, we found that the number of TUJ1- and NF-positive cells was significantly increased from U18-treated WT- and NPC-iNSCs compared to non-treated WT-cells (Figure 6A-6C)
Summary
Niemann-Pick disease type C (NPC) is an autosomal recessive and neurodegenerative disease caused by mutations in either the NPC1 (95% of cases) or the NPC2 gene (5% of cases) [1]. Over 250 different types of mutations affecting protein expression, function and stability have been identified in the NPC1 gene. The most common mutation, NPC1I1061T, www.impactjournals.com/oncotarget represents 15-20% of all disease alleles and associated with the classic juvenile-onset phenotype of NPC disease. NPC1I1061T mutation disrupts NPC1 protein trafficking and mutant protein is endoplasmic reticulum (ER) retained and targeted for degradation [2]. Defects in NPC proteins lead to impaired intracellular cholesterol trafficking, followed by the accumulation of unesterified cholesterol and sphingolipids in various organs [3]. All NPC patients develop neurological symptoms, which result in disability and death, so many attempts have been made to reveal the pathogenic mechanisms [5]
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