Department of Cell Research and Immunology, Tel Aviv University, Ramat Aviv, Israel.
Blood Cells Mol Dis. 2013 Feb;50(2):141-5. doi: 10.1016/j.bcmd.2012.10.007. Epub 2012 Nov 14.
Gaucher disease (GD) is characterized by accumulation of glucosylceramide in lysosomes due to mutations in the GBA1 gene encoding the lysosomal hydrolase β-glucocerebrosidase (GCase). The disease has a broad spectrum of phenotypes, which were divided into three different Types; Type 1 GD is not associated with primary neurological disease while Types 2 and 3 are associated with central nervous system disease. GCase molecules are synthesized on endoplasmic reticulum (ER)-bound polyribosomes, translocated into the ER and following modifications and correct folding, shuttle to the lysosomes. Mutant GCase molecules, which fail to fold correctly, undergo ER associated degradation (ERAD) in the proteasomes, the degree of which is one of the factors that determine GD severity. Several pharmacological chaperones have already been shown to assist correct folding of mutant GCase molecules in the ER, thus facilitating their trafficking to the lysosomes. Ambroxol, a known expectorant, is one such chaperone. Here we show that ambroxol increases both the lysosomal fraction and the enzymatic activity of several mutant GCase variants in skin fibroblasts derived from Type 1 and Type 2 GD patients.
戈谢病（GD）的特征是由于编码溶酶体水解酶β-葡糖苷脑苷脂酶（GCase）的 GBA1 基因突变，导致葡萄糖脑苷脂在溶酶体中积累。该疾病具有广泛的表型，分为三种不同类型；1 型 GD 与原发性神经疾病无关，而 2 型和 3 型与中枢神经系统疾病有关。GCase 分子在内质网（ER）结合的多核糖体上合成，易位到 ER 中，并在经过修饰和正确折叠后，穿梭到溶酶体中。未能正确折叠的突变 GCase 分子在蛋白酶体中经历 ER 相关降解（ERAD），其程度是决定 GD 严重程度的因素之一。已经有几种药理学伴侣被证明可以协助 ER 中突变 GCase 分子的正确折叠，从而促进它们向溶酶体的运输。氨溴索是一种已知的祛痰药，就是这样一种伴侣。在这里，我们证明氨溴索增加了源自 1 型和 2 型 GD 患者的皮肤成纤维细胞中几种突变 GCase 变体的溶酶体分数和酶活性。
