Morphological Alterations of the Cornea in the Mouse Model of Niemann–Pick Disease Type C1


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Abstract

Purpose:Niemann-Pick disease type C1 (NPC1) is a genetic neurovisceral disorder characterized by abnormalities in intracellular sterol trafficking. A knockout mouse model (NPC1−/−) is an important tool for the study of pathogenesis and treatment strategies. In the present study, NPC1−/− mice were examined for pathological changes in the cornea.Methods:Fifteen inbred homozygous NPC1 knockout mice (NPC1−/−, 5-10 weeks old), 5 age-matched heterozygous mice (NPC1+/−), and 14 wild-type control mice (NPC1+/+) were examined. In vivo confocal laser scanning microscopy (CLSM) was performed on both eyes of each animal; afterward, the eyes were processed for histology, electron microscopy, and lipid analysis.Results:In vivo CLSM disclosed hyperreflective intracellular deposits in the intermediate and basal cell layers of corneal epithelium in all NPC1−/− mice. At the electron microscopy level, however, vacuolated cytoplasmic structures, 200-500 nm in diameter, with electron-dense material appeared in all structures investigated, including all epithelial layers and stromal keratocytes. These deposits were negative for filipin, a marker for unesterified cholesterol. Lipid analysis showed a marked increase in disialotetrahexosylganglioside 2 (GM2) level in NPC1−/− mice corneas, whereas no changes were detected in free cholesterol and disialotetrahexosylganglioside 3 (GM3) levels when compared with controls.Conclusions:Morphological changes characteristic for the NPC1−/− mouse cornea were visualized in all epithelial layers and keratocytes. In vivo CLSM findings were confirmed by other techniques. In vivo detection of ocular manifestations and analysis of ocular tissue have the potential to aid the diagnosis of NPC1 disease and to monitor the efficacy of treatment.

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