Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease

Pramod K. Mistry; Jun Liu; Li SunWei-Lien ChuangTony YuenRuhua YangPing LuKate ZhangJianhua LiJoan KeutzerAgnes StachnikAlbert MennoneJames L. BoyerDhanpat JainRoscoe O. BradyMaria I. NewMone Zaidi

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Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease

机译：Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease

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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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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第13期|4934-4939|共6页
作者
Pramod K. Mistry; Jun Liu; Li SunWei-Lien ChuangTony YuenRuhua YangPing LuKate ZhangJianhua LiJoan KeutzerAgnes StachnikAlbert MennoneJames L. BoyerDhanpat JainRoscoe O. BradyMaria I. NewMone Zaidi;
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作者单位

Department of Medicine, Yale School of Medicine, New Haven, CT 06520;

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20824;

Mount Sinai Bone Program,Mount Sinai School of Medicine, New York, NY 10029Genzyme Sanofi, Framingham, MA 01701;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
macrophage; knockout mice; S1P;

Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease

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