Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage
Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage
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DOI：
10.1073/pnas.1003308107
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发表时间：
2010-11-09
影响因子：
11.1
通讯作者：
Zaidi, Mone
中科院分区：
文献类型：
--
作者：
Mistry, Pramod K.;Liu, Jun;Zaidi, Mone
在非神经元病性1型戈谢病（GD 1）中，葡萄糖脑苷脂酶基因（GBA 1）突变导致葡萄糖脑苷脂酶缺乏及其底物葡萄糖脑苷脂（GL-1）在单核吞噬细胞溶酶体中蓄积。然而，这种流行的以巨噬细胞为中心的观点并不能解释疾病的新方面，包括恶性肿瘤，自身免疫性疾病，帕金森病和骨质疏松症。我们使用Mx 1启动子有条件地删除了造血和间充质细胞谱系中的GBA 1基因。尽管这只小鼠完全重现了人GD 1，但细胞因子测量、微阵列分析和细胞免疫表型分析一起揭示了不仅巨噬细胞，而且胸腺T细胞、树突状细胞和成骨细胞的广泛功能障碍。严重的骨质疏松症是由成骨细胞骨形成缺陷引起的，该缺陷是由蓄积的脂质LysoGL-1和GL-1对蛋白激酶C的抑制作用引起的。这项研究提供了直接的证据，参与GD 1的多个细胞谱系，表明细胞以外的巨噬细胞可能是有价值的治疗目标。
In nonneuronopathic type 1 Gaucher disease (GD1), mutations in the glucocerebrosidase gene (GBA1) gene result in glucocerebrosidase deficiency and the accumulation of its substrate, glucocerebroside (GL-1), in the lysosomes of mononuclear phagocytes. This prevailing macrophage-centric view, however, does not explain emerging aspects of the disease, including malignancy, autoimmune disease, Parkinson disease, and osteoporosis. We conditionally deleted the GBA1 gene in hematopoietic and mesenchymal cell lineages using an Mx1 promoter. Although this mouse fully recapitulated human GD1, cytokine measurements, microarray analysis, and cellular immunophenotyping together revealed widespread dysfunction not only of macrophages, but also of thymic T cells, dendritic cells, and osteoblasts. The severe osteoporosis was caused by a defect in osteoblastic bone formation arising from an inhibitory effect of the accumulated lipids LysoGL-1 and GL-1 on protein kinase C. This study provides direct evidence for the involvement in GD1 of multiple cell lineages, suggesting that cells other than macrophages may be worthwhile therapeutic targets.