CONSEQUENCES OF BETA-GLUCOCEREBROSIDASE DEFICIENCY IN EPIDERMIS - ULTRASTRUCTURE AND PERMEABILITY BARRIER ALTERATIONS IN GAUCHER DISEASE
CONSEQUENCES OF BETA-GLUCOCEREBROSIDASE DEFICIENCY IN EPIDERMIS - ULTRASTRUCTURE AND PERMEABILITY BARRIER ALTERATIONS IN GAUCHER DISEASE
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DOI：
10.1172/jci117160
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发表时间：
1994-04-01
影响因子：
15.9
通讯作者：
SIDRANSKY, E
中科院分区：
文献类型：
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作者：
HOLLERAN, WM;GINNS, EI;SIDRANSKY, E
β-葡萄糖脑苷脂酶水解葡萄糖神经酰胺产生神经酰胺，神经酰胺是介导表皮渗透屏障的细胞间层的关键成分。 2 型戈谢病患者的一部分表现出鱼鳞病样皮肤异常，无效等位基因纯合的转基因戈谢病小鼠也是如此。为了研究葡萄糖脑苷脂酶缺乏与表皮通透性屏障功能之间的关系，我们将戈谢小鼠与携带者和正常小鼠以及局部用葡萄糖脑苷脂酶不可逆抑制剂溴Conduritol B环氧化物（BrCBE）治疗的无毛小鼠的角质层（SC）超微结构、脂质含量和屏障功能进行了比较。 Gaucher 小鼠和 BrCBE 处理的小鼠在整个 SC 间隙中都显示出异常的、不完全加工的层状体衍生片层，而转基因载体小鼠则显示出正常的双层。一名严重受影响的 2 型戈谢病婴儿的 SC 也显示出类似的超微结构异常。此外，戈谢小鼠表现出显着升高的经皮失水量（4.2+/-0.6 vs < 0.10 g/m(2)/h）。电子致密示踪剂胶体镧仅在戈谢小鼠 SC 间隙中未完全加工的层状体衍生片之间渗透，表明渗透性屏障功能发生了改变。 Gaucher 和 BrCBE 处理的小鼠分别表现出正常表皮葡萄糖脑苷脂酶活性的 < 1% 和 < 5%，并且 Gaucher 小鼠的表皮/SC 表现出葡萄糖神经酰胺升高（5 至 10 倍），神经酰胺含量减少。因此，在戈谢小鼠和婴儿中观察到的皮肤变化可能是由于葡萄糖神经酰胺水解成神经酰胺的减少而形成无能的细胞间层状双层的结果。因此，葡萄糖脑苷脂酶对于生成具有足够功能能力的表皮屏障功能的膜来说似乎是必需的。
Hydrolysis of glucosylceramide by beta-glucocerebrosidase results in ceramide, a critical component of the intercellular lamellae that mediate the epidermal permeability barrier. A subset of type 2 Gaucher patients displays ichthyosiform skin abnormalities, as do transgenic Gaucher mice homozygous for a null allele. To investigate the relationship between glucocerebrosidase deficiency and epidermal permeability barrier function, we compared the stratum corneum (SC) ultrastructure, lipid content, and barrier function of Gaucher mice to carrier and normal mice, and to hairless mice treated topically with bromoconduritol B epoxide (BrCBE), an irreversible inhibitor of glucocerebrosidase. Both Gaucher mice and BrCBE-treated mice revealed abnormal, incompletely processed, lamellar body-derived sheets throughout the SC interstices, while transgenic carrier mice displayed normal bilayers. The SC of a severely affected type 2 Gaucher's disease infant revealed similarly abnormal ultrastructure. Furthermore, the Gaucher mice demonstrated markedly elevated transepidermal water loss (4.2+/-0.6 vs < 0.10 g/m(2) per h). The electron-dense tracer, colloidal lanthanum, percolated between the incompletely processed lamellar body-derived sheets in the SC interstices of Gaucher mice only, demonstrating altered permeability barrier function. Gaucher and BrCBE-treated mice showed < 1% and < 5% of normal epidermal glucocerebrosidase activity, respectively, and the epidermis/SC of Gaucher mice demonstrated elevated glucosylceramide (5- to 10-fold), with diminished ceramide content. Thus, the skin changes observed in Gaucher mice and infants may result from the formation of incompetent intercellular lamellar bilayers due to a decreased hydrolysis of glucosylceramide to ceramide. Glucocerebrosidase therefore appears necessary for the generation of membranes of sufficient functional competence for epidermal barrier function.