STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES

Tay-Sachs和Sandhoff病是严重的神经退行性疾病 其特征在于作为结果受损的GM 2神经节苷脂降解 β-氨基己糖苷酶A缺乏症 HEXA和HEXB突变 编码β-氨基己糖苷酶A亚基的基因导致Tay- 萨克斯和山德霍夫病。 在人类中， 两种疾病的表型和神经病理学非常相似。 通过破坏胚胎干细胞中的Hexa和Hexb基因， 我们建立了相应的Tay-Sachs和Sandhoff小鼠模型 疾病 破坏的Hexa或Hexb基因纯合子小鼠 缺乏β-氨基己糖苷酶A， 大脑 然而，与Tay-Sachs和Sandhoff病患者不同， Hexa和Hexb“敲除”小鼠显示出非常不同的表型。 的 Hexa基因敲除小鼠的寿命正常（约2年）， 神经系统异常 相比之下，Hexb基因敲除小鼠 严重影响。 从大约3.5个月开始，这些动物表现出 进行性步态异常、肌肉萎缩和痉挛。 了5 几个月后，这些动物几乎完全瘫痪。 一致 与不同表型相关的是， 两种突变小鼠的储存神经元。 在Hexb淘汰赛中 在小鼠中枢神经系统的几乎所有神经元中观察到储存 系统 相反，在Hexa基因敲除小鼠中， 大脑的某些区域。 根据表型差异， 值得注意的是，小脑浦肯野区存在显著的储存， 细胞和脊髓运动神经元中的Hexb，但不是Hexa 基因敲除小鼠 此外，我们还发现， 两种小鼠模型之间的差异是由于 神经节苷脂降解途径之间的小鼠和人类。

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.