STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES

泰-萨克斯病和桑德霍夫病是严重的神经退行性疾病 以GM2神经节苷脂降解受损为特征 β-氨基己糖苷酶A缺乏症。HEXA和HEXB基因突变 编码β-己糖苷酶A亚单位的基因会导致Tay-Tay- 分别为萨克斯病和桑德霍夫病。在人类中，神经学 这两种疾病的表型和神经病理非常相似。 通过破坏胚胎干细胞中的HexA和Hexb基因， 我们已经建立了对应于泰-萨克斯和桑德霍夫的小鼠模型 疾病。突变的HexA或HexB基因纯合的小鼠 缺乏β-己糖苷酶A和积聚的GM2 大脑。然而，与泰-萨克斯和桑德霍夫病患者不同的是， Hexa和Hexb“敲除”小鼠表现出非常不同的表型。这个 六基因敲除小鼠有正常的寿命(大约两年)，并且没有表现出 神经学异常。相比之下，Hexb基因敲除的小鼠 受到严重影响。从大约3.5个月开始，这些动物表现出 步态逐渐异常，肌肉萎缩和痉挛。乘以5 几个月后，这些动物表现出几乎完全的肢体瘫痪。一致 随着表型的不同，它们的数量和分布也不同 在这两种类型的突变小鼠中储存神经元。在Hexb淘汰赛中 在中枢神经的几乎所有神经元中都观察到了老鼠的储存。 系统。相反，在Hexa基因敲除的小鼠中，储存受到限制 到大脑的某些区域。根据表型差异， 值得注意的是，在小脑浦肯野发现了显著的存储 Hexb中的细胞和脊髓运动神经元，而不是Hexa中的 基因敲除的老鼠。此外，我们还发现，表型差异 这两种小鼠模型之间的差异是由于 神经节苷脂在小鼠和人之间的降解途径。

Tay-Sachs and Sandhoff diseases are severe neurodegenerative disorders characterized by impaired GM2 ganglioside degradation as a consequence of beta-hexosaminidase A deficiency. Mutations in the HEXA and HEXB genes, which encode the subunits of beta-hexosaminidase A, cause Tay- Sachs and Sandhoff disease, respectively. In humans, the neurologic phenotype and neuropathology in the two diseases are very similar. Through disruption of the Hexa and Hexb genes in embryonic stem cells, we have established mouse models corresponding to Tay-Sachs and Sandhoff diseases. Mice homozygous for either the disrupted Hexa or Hexb gene were deficient in beta-hexosaminidase A and accumulated GM2 in their brains. However, unlike Tay-Sachs and Sandhoff disease patients, the Hexa and Hexb "knock-out" mice displayed very different phenotypes. The Hexa knock-out mice had a normal life span (about 2 years) and showed no neurologic abnormalities. In contrast, the Hexb knock-out mice were severely affected. Beginning at about 3.5 months these animals showed progressive gait abnormalities, muscle wasting and spasticity. By 5 months the animals displayed nearly complete limb paralysis. Consistent with the different phenotypes were athe number and distribution of storage neurons in the two types of mutant mice. In the Hexb knock-out mice storage was observed in almost all neurons in the central nervous system. In contrast, in the Hexa knock-out mice storage was restricted to certain regions of the brain. In light of the phenotypic difference, it is notable the significant storage was found in cerebellar Purkinje cells and in the spinal cord motor neurons in the Hexb but not the Hexa knock-out mice. Furthermore, we have found that phenotypic difference between the two mouse models is the result of differences in the ganglioside degradation pathway between mice and humans.