Glycosphingolipid degradation and animal models of GM2-gangliosidoses
Glycosphingolipid degradation and animal models of GM2-gangliosidoses
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DOI：
10.1023/a:1005419122018
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发表时间：
1998-08-01
影响因子：
4.2
通讯作者：
Sandhoff, K
中科院分区：
文献类型：
--
作者：
Kolter, T;Sandhoff, K
鞘糖脂在真核细胞表面形成细胞类型特异性图案。鞘糖脂的降解需要质膜源性鞘糖脂的内吞膜流进入溶酶体作为消化细胞器。溶酶体水解酶和鞘脂激活蛋白的遗传性缺陷都可引起鞘脂蓄积性疾病。近年来的研究主要集中在溶酶体选择性膜降解的机制以及鞘脂激活蛋白的机制和生理功能。gm2降解系统是激活蛋白依赖性溶酶体降解的范例。有三条多肽链参与神经节苷脂GM2的体内降解：β -己糖氨酸酶的α -链和β -链以及GM2激活剂。已经描述了Tay-Sachs病（α -链缺乏症）、Sandhoff病（β -链缺乏症）和GM2激活剂缺乏症的小鼠模型。虽然这些gm2 -神经节脂质剂量变异的表型在人类中仅略有不同，但动物模型显示疾病的严重程度和病程存在巨大差异；其原因是唾液酸酶的特异性，这在小鼠和人之间是不同的。缺乏己糖氨酸酶A、B和S的双敲除小鼠表现为粘多糖病和神经节脂质沉积症。底物剥夺方法治疗讨论了gm2神经节苷脂剂量的动物模型。
Glycosphingolipids form cell type-specific patterns on the surface of eukaryotic cells. Degradation of glycosphingolipids requires endocytic membrane flow of plasma membrane-derived glycosphingolipids into the lysosomes as the digesting organelles. The inherited deficiencies of lysosomal hydrolases and of sphingolipid activator proteins both give rise to sphingolipid storage diseases. Recent research has focused on the mechanisms leading to selective membrane degradation in the lysosomes and on the mechanism and physiological function of sphingolipid activator proteins. The GM2-degrading system is a paradigm for activator protein-dependent lysosomal degradation. Three polypeptide chains contribute to the in vivo degradation of ganglioside GM2: the alpha- and beta-chains of the beta-hexosaminidases and the GM2 activator. Mouse models of Tay-Sachs disease (alpha-chain deficiency), Sandhoff disease (beta-chain deficiency) and GM2 activator deficiency have been described. While the phenotypes of these variants of GM2-gangliosidoses are only slightly different in humans, the animal models show drastic differences in severity and course of the diseases; The reason for this is the specificity of sialidase, which is different between mouse and human. A double-knockout mouse lacking hexosaminidases A, B and S shows a phenotype of mucopolysaccharidosis and gangliosidosis. A substrate deprivation approach to therapy is discussed with respect to animal models of the GM2-gangliosidoses.