ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity
ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity
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DOI：
10.1093/hmg/ddi240
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发表时间：
2005-08-15
影响因子：
3.5
通讯作者：
Horowitz, M
中科院分区：
文献类型：
--
作者：
Ron, I;Horowitz, M
戈谢病（GD）是一种常染色体隐性遗传病，其特征是由于酸性β-葡萄糖脑苷脂酶基因突变，葡萄糖神经酰胺主要在网状内皮系统细胞中蓄积。一些患者患有神经系统症状（2型和3型患者），而I型GD患者不存在神经系统体征。即使在具有相同基因型的患者中，该疾病也是异质性的，这意味着葡萄糖脑苷脂酶基因的突变是导致GD所必需的，但其他因素在该疾病的表现中起重要作用。葡萄糖脑苷脂酶是一种溶酶体酶，在内质网（ER）结合的多聚核糖体上合成并转运到ER中。在Winked糖基化之后，它被转运到高尔基体，从那里它被运输到溶酶体。在这项研究中，我们检测了GD患者皮肤成纤维细胞中葡萄糖脑苷脂酶蛋白水平、N-聚糖加工和细胞内定位。我们的研究结果强烈表明，突变葡萄糖脑苷脂酶变体呈现不同水平的ER保留，并在蛋白酶体中发生ER相关降解。ER滞留和蛋白酶体降解的程度是决定GD严重程度的因素之一。
Gaucher disease (GD), an autosomal recessive disease, is characterized by accumulation of glucosylceramide mainly in cells of the reticuloendothelial system, due to mutations in the acid beta-glucocerebrosidase gene. Some of the patients suffer from neurological symptoms (type 2 and type 3 patients), whereas patients with type I GD do not present neurological signs. The disease is heterogeneous even among patients with the same genotype, implicating that a mutation in the glucocerebrosidase gene is required to cause GD but other factors play an important role in the manifestation of the disease. Glucocerebrosidase is a lysosomal enzyme, synthesized on endoplasmic reticulum (ER)-bound polyribosomes and translocated into the ER. Following Winked glycosylations, it is transported to the Golgi apparatus, from where it is trafficked to the lysosomes. In this study, we tested glucocerebrosidase protein levels, N-glycans processing and intracellular localization in skin fibroblasts derived from patients with GD. Our results strongly suggest that mutant glucocerebrosidase variants present variable levels of ER retention and undergo ER-associated degradation in the proteasomes. The degree of ER retention and proteasomal degradation is one of the factors that determine GD severity.