National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan.
PLoS One. 2013 Aug 2;8(8):e69147. doi: 10.1371/journal.pone.0069147. Print 2013.
Gaucher disease (GD) is the most common of the lysosomal storage disorders and is caused by defects in the GBA gene encoding glucocerebrosidase (GlcCerase). The accumulation of its substrate, glucocylceramide (GlcCer) is considered the main cause of GD. We found here that the expression of human mutated GlcCerase gene (hGBA) that is associated with neuronopathy in GD patients causes neurodevelopmental defects in Drosophila eyes. The data indicate that endoplasmic reticulum (ER) stress was elevated in Drosophila eye carrying mutated hGBAs by using of the ER stress markers dXBP1 and dBiP. We also found that Ambroxol, a potential pharmacological chaperone for mutated hGBAs, can alleviate the neuronopathic phenotype through reducing ER stress. We demonstrate a novel mechanism of neurodevelopmental defects mediated by ER stress through expression of mutants of human GBA gene in the eye of Drosophila.
戈谢病（GD）是溶酶体贮积症中最常见的一种，由编码葡萄糖脑苷脂酶（GlcCerase）的 GBA 基因突变引起。其底物葡萄糖脑苷脂（GlcCer）的积累被认为是 GD 的主要原因。我们在这里发现，与 GD 患者神经元病变相关的人类突变型 GlcCerase 基因（hGBA）的表达会导致果蝇眼睛的神经发育缺陷。数据表明，通过使用内质网应激标志物 dXBP1 和 dBiP，携带突变 hGBAs 的果蝇眼睛中的内质网（ER）应激升高。我们还发现，氨溴索作为突变型 hGBAs 的潜在药理学伴侣，可以通过降低 ER 应激来减轻神经元病变表型。我们通过在果蝇眼睛中表达人类 GBA 基因突变体，证明了一种通过 ER 应激介导的神经发育缺陷的新机制。
