Abstract
Niemann–Pick disease type C (NPC) is an autosomal recessive disorder characterized by abnormal accumulation of free cholesterol and sphingolipids in lysosomes. The iminosugar miglustat, which inhibits hexosylceramide synthesis, is used for NPC treatment, and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), a cyclic oligosaccharide derivative, is being developed to treat NPC. Moreover, therapeutic potential of 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD) was shown in NPC models, although its mechanism of action remains unclear. Here, we investigated the effects of HP-β-CD, HP-γ-CD, and their homolog 2-hydroxypropyl-α-cyclodextrin (HP-α-CD) on lipid accumulation in Npc1-null Chinese hamster ovary (CHO) cells compared with those of miglustat. HP-β-CD and HP-γ-CD, unlike HP-α-CD, reduced intracellular free cholesterol levels and normalized the lysosome changes in Npc1-null cells but not in wild-type CHO cells. In contrast, miglustat did not normalize intracellular free cholesterol accumulation or lysosome changes in Npc1-null cells. However, miglustat decreased the levels of hexosylceramide and tended to increase those of sphingomyelins in line with its action as a glucosylceramide synthase inhibitor in both Npc1-null and wild-type CHO cells. Interestingly, HP-β-CD and HP-γ-CD, unlike HP-α-CD, reduced sphingomyelins in Npc1-null, but not wild-type, cells. In conclusion, HP-β-CD and HP-γ-CD reduce the accumulation of sphingolipids, mainly sphingomyelins, and free cholesterol as well as lysosome changes in Npc1-null, but not in wild-type, CHO cells.
Highlights
Niemann–Pick disease type C (NPC) is a rare autosomal recessive disease resulting in a lysosomal lipid trafficking dysfunction caused by mutations in either of the two genes encoding lipid-transporting proteins, NPC1 or NPC2 (95% and 5% of patients, respectively) [1,2,3]
We demonstrated that HP-β-CD and HP-γ-CD attenuate the increase in LysoTracker® fluorescence intensity and the abnormal cholesterol trafficking in Npc1-null Chinese hamster ovary (CHO) cells and neural and hepatocyte progenitors derived from induced pluripotent stem cell lines from NPC patients [23,28]
We found that HP-β-CD and HP-γ-CD, but not HP-α-CD, significantly attenuated sphingolipid accumulation, sphingomyelins, as well as free cholesterol accumulation and lysosomal expansion in Npc1-null CHO cells
Summary
Niemann–Pick disease type C (NPC) is a rare autosomal recessive disease resulting in a lysosomal lipid trafficking dysfunction caused by mutations in either of the two genes encoding lipid-transporting proteins, NPC1 or NPC2 (95% and 5% of patients, respectively) [1,2,3]. Dysfunction of the NPC1/2 protein disrupts this transport system, leading to abnormal accumulation of cholesterol and sphingolipids in endolysosomal compartments. This results in manifestations such as neurological dysfunction and liver and lung failure [1,6]. N-butyl-deoxynojirimycin, is an approved drug for the treatment of NPC in Europe, Canada, and Japan, which inhibits the rate-determining enzyme for glucosylceramide synthesis hexosylceramide synthase. It reduces the intracellular levels of hexosylceramide as well as of GM2 and GM3 gangliosides. Colaco et al [15] reported that miglustat appears to have a therapeutic potential against Tangier disease, a metabolic disease caused by a defect in ATP-binding cassette transporter 1, which can be misdiagnosed as NPC
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