Murine models of acute neuronopathic Gaucher disease
Murine models of acute neuronopathic Gaucher disease
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DOI：
10.1073/pnas.0708086104
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发表时间：
2007-10-30
影响因子：
11.1
通讯作者：
Karlsson, Stefan
中科院分区：
文献类型：
--
作者：
Enquist, Ida Berglin;Lo Bianco, Christophe;Karlsson, Stefan
戈谢病（GD）是一种常染色体隐性溶酶体贮积症，由编码溶酶体酶-糖基神经酰胺酶（GCase）的葡萄糖苷酶- β -酸（GBA）基因突变引起。GCase缺乏导致特征性的内脏病理，并在一些患者中导致致命的神经系统表现。在这里，我们报告了具有严重神经病变形式的GD的小鼠模型的生成。为了避免在先前的几种GCase缺陷动物中观察到的致死性皮肤表型，我们对小鼠模型进行了基因工程改造，使其除皮肤外的所有组织中GCase活性都明显降低。这些小鼠表现出与严重神经变性和脑内凋亡细胞死亡相关的快速运动功能障碍，使人联想到神经性GD。此外，我们已经建立了第二个小鼠模型，其中GCase缺陷仅限于神经和胶质细胞祖细胞和后代。这些小鼠的病理与第一个小鼠模型相似，但发病延迟，疾病进展缓慢，这表明造血来源的小胶质细胞中GCase缺乏并不是中枢神经系统病理的主要决定因素。这些发现也表明正常的小胶质细胞不能挽救这种神经退行性疾病。这些小鼠模型对神经性GD患者的治疗发展具有重要意义。
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the glucosidase, beta, acid (GBA) gene that encodes the lysosomal enzyme glucosylceramidase (GCase). GCase deficiency leads to characteristic visceral pathology and, in some patients, lethal neurological manifestations. Here, we report the generation of mouse models with the severe neuronopathic form of GD. To circumvent the lethal skin phenotype observed in several of the previous GCase-deficient animals, we genetically engineered a mouse model with strong reduction in GCase activity in all tissues except the skin. These mice exhibit rapid motor dysfunction associated with severe neurodegeneration and apoptotic cell death within the brain, reminiscent of neuronopathic GD. In addition, we have created a second mouse model, in which GCase deficiency is restricted to neural and glial cell progenitors and progeny. These mice develop similar pathology as the first mouse model, but with a delayed onset and slower disease progression, which indicates that GCase deficiency within microglial cells that are of hematopoietic origin is not the primary determinant of the CNS pathology. These findings also demonstrate that normal microglial cells cannot rescue this neurodegenerative disease. These mouse models have significant implications for the development of therapy for patients with neuronopathic GD.