Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase.
Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase.
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DOI：
10.1016/j.bcmd.2012.10.007
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发表时间：
2013-02
影响因子：
2.3
通讯作者：
Horowitz, Mia
中科院分区：
文献类型：
--
作者：
Bendikov-Bar, Inna;Maor, Gali;Filocamo, Mirella;Horowitz, Mia
Gaucher疾病（GD）的特征是，由于编码溶酶体水解酶β-葡萄糖酶酶（GCASE）的GBA1基因中的突变，葡萄糖基酶在溶酶体中积累GD与原发性神经疾病无关，而第2型和3型与中枢神经系统疾病有关在内质网（ER） - 结合多核糖体上合成，翻译成ER并进行了修改，并正确折叠，穿梭到溶酶体，这些突变体GCASE分子无法正确折叠，在蛋白酶中均未经历ER相关的降解（ERAD）其中是决定GD严重程度的因素之一。
已经证明了几种药物链，可以有助于纠正ER中突变的GCASE分子，从而支持其对溶酶体的运输，这是一种已知的预期。来自1型和2型GD患者的皮肤成纤维细胞中几种突变GCASE变体的酶促活性。
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.
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