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PNAS:I型戈谢病的可能的药物靶标

来源:EurekAlert 2014-03-18 09:37

科研人员报告说,删除为患有I型戈谢病的小鼠的葡萄糖脑苷脂酶(GBA2)编码的一个基因,能阻止这种疾病的进展,这提示葡萄糖脑苷脂酶(GBA2)是药物疗法治疗人类I型戈谢病的一个可能的靶标。I型戈谢病是一种脂类在细胞中积累的罕见遗传病。(生物谷Bioon.com)

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Proceedings of the National Academy of the Sciences of the United States of America           doi: 10.1073/pnas.1400768111

Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease

Pramod K. Mistrya,1, Jun Liua,2, Li Sunb,c,2, Wei-Lien Chuangd, Tony Yuenb,c,e, Ruhua Yanga, Ping Lub,c, Kate Zhangd, Jianhua Lib,c, Joan Keutzerd, Agnes Stachnikb,c, Albert Mennonea, James L. Boyera, Dhanpat Jaina, Roscoe O. Bradyf, Maria I. Newb,e,1, and Mone Zaidib,c,1

The inherited deficiency of the lysosomal glucocerebrosidase (GBA) due to mutations in the GBA gene results in Gaucher disease (GD). A vast majority of patients present with nonneuronopathic, type 1 GD (GD1). GBA deficiency causes the accumulation of two key sphingolipids, glucosylceramide (GL-1) and glucosylsphingosine (LysoGL-1), classically noted within the lysosomes of mononuclear phagocytes. How metabolites of GL-1 or LysoGL-1 produced by extralysosomal glucocerebrosidase GBA2 contribute to the GD1 pathophysiology is not known. We recently recapitulated hepatosplenomegaly, cytopenia, hypercytokinemia, and the bone-formation defect of human GD1 through conditional deletion of Gba in Mx1–Cre+:GD1 mice. Here we show that the deletion of Gba2 significantly rescues the GD1 clinical phenotype, despite enhanced elevations in GL-1 and LysoGL-1. Most notably, the reduced bone volume and bone formation rate are normalized. These results suggest that metabolism of GL-1 or LysoGL-1 into downstream bioactive lipids is a major contributor to the bone-formation defect. Direct testing revealed a strong inhibition of osteoblast viability by nanomolar concentrations of sphingosine, but not of ceramide. These findings are consistent with toxicity of high circulating sphingosine levels in GD1 patients, which decline upon enzyme-replacement therapy; serum ceramide levels remain unchanged. Together, complementary results from mice and humans affected with GD1 not only pinpoint sphingosine as being an osteoblast toxin, but also set forth Gba2 as a viable therapeutic target for the development of inhibitors to ameliorate certain disabling consequences of GD1. 

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