Accumulation of Ordered Ceramide-Cholesterol Domains in Farber Disease Fibroblasts
Accumulation of Ordered Ceramide-Cholesterol Domains in Farber Disease Fibroblasts
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DOI：
10.1007/8904_2013_246
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发表时间：
2014-01-01
期刊：
影响因子：
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通讯作者：
Futerman, Anthony H.
中科院分区：
文献类型：
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作者：
Ferreira, Natalia Santos;Goldschmidt-Arzi, Michal;Futerman, Anthony H.
法伯病是由酸性神经酰胺酶基因突变引起的遗传性代谢紊乱，其导致神经酰胺在溶酶体中积聚。法伯病患者表现出各种各样的症状，大多数患者最终表现出神经系统功能障碍的迹象。我们现在提出了一种新的工具，可以潜在地用于区分疾病的温和和更严重的形式，即，识别混合单层或双层胆固醇的抗体：C16-神经酰胺，但不识别神经酰胺或胆固醇本身。该抗体以前已被用于检测胆固醇：C16-神经酰胺结构域在各种培养细胞。我们证明，胆固醇水平：C16-神经酰胺域显着升高，从4型和7型法伯病患者的成纤维细胞，和域的水平可以通过降低神经酰胺或胆固醇水平进行调制。此外，这些结构域位于内膜系统的膜中，并且还位于两个意想不到的位置，即线粒体和质膜。这项研究表明，在严重形式的法伯病细胞中积累的神经酰胺被隔离到不同的膜子域，这可能解释了在这种毁灭性的溶酶体贮积病中观察到的一些细胞病理学。
Farber disease is an inherited metabolic disorder caused by mutations in the acid ceramidase gene, which leads to ceramide accumulation in lysosomes. Farber disease patients display a wide variety of symptoms with most patients eventually displaying signs of nervous system dysfunction. We now present a novel tool that could potentially be used to distinguish between the milder and more severe forms of the disease, namely, an antibody that recognizes a mixed monolayer or bilayer of cholesterol: C16-ceramide, but does not recognize either ceramide or cholesterol by themselves. This antibody has previously been used to detect cholesterol: C16-ceramide domains in a variety of cultured cells. We demonstrate that levels of cholesterol: C16-ceramide domains are significantly elevated in fibroblasts from types 4 and 7 Farber disease patients, and that levels of the domains can be modulated by either reducing ceramide or cholesterol levels. Moreover, these domains are located in membranes of the endomembrane system, and also in two unexpected locations, namely, the mitochondria and the plasma membrane. This study suggests that the ceramide that accumulates in severe forms of Farber disease cells is sequestered to distinct membrane subdomains, which may explain some of the cellular pathology observed in this devastating lysosomal storage disease.