Phaneuf D, Wakamatsu N, Huang J Q, Borowski A, Peterson A C, Fortunato S R, Ritter G, Igdoura S A, Morales C R, Benoit G, Akerman B R, Leclerc D, Hanai N, Marth J D, Trasler J M, Gravel R A
Department of Pediatrics, McGill University, Montreal, Canada.
Hum Mol Genet. 1996 Jan;5(1):1-14. doi: 10.1093/hmg/5.1.1.
We have generated mouse models of human Tay-Sachs and Sandhoff diseases by targeted disruption of the Hexa (alpha subunit) or Hexb (beta subunit) genes, respectively, encoding lysosomal beta-hexosaminidase A (structure, alpha) and B (structure, beta beta). Both mutant mice accumulate GM2 ganglioside in brain, much more so in Hexb -/- mice, and the latter also accumulate glycolipid GA2. Hexa -/- mice suffer no obvious behavioral or neurological deficit, while Hexb -/- mice develop a fatal neurodegenerative disease, with spasticity, muscle weakness, rigidity, tremor and ataxia. The Hexb -/- but not the Hexa -/- mice have massive depletion of spinal cord axons as an apparent consequence of neuronal storage of GM2. We propose that Hexa -/- mice escape disease through partial catabolism of accumulated GM2 via GA2 (asialo-GM2) through the combined action of sialidase and beta-hexosaminidase B.
我们分别通过靶向破坏编码溶酶体β-己糖胺酶A（结构，α）和B（结构，ββ）的Hexa（α亚基）或Hexb（β亚基）基因，生成了人类泰-萨克斯病和桑德霍夫病的小鼠模型。两种突变小鼠在大脑中均积累GM2神经节苷脂，在Hexb -/-小鼠中积累得更多，并且后者还积累糖脂GA2。Hexa -/-小鼠没有明显的行为或神经功能缺陷，而Hexb -/-小鼠则发展为致命的神经退行性疾病，伴有痉挛、肌肉无力、僵硬、震颤和共济失调。Hexb -/-小鼠而非Hexa -/-小鼠出现脊髓轴突大量消耗，这显然是GM2在神经元中蓄积的结果。我们提出，Hexa -/-小鼠通过唾液酸酶和β-己糖胺酶B的联合作用，经由GA2（脱唾液酸GM2）对蓄积的GM2进行部分分解代谢，从而避免发病。
