Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases
Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases
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DOI：
10.1093/hmg/5.1.1
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发表时间：
1996-01-01
影响因子：
3.5
通讯作者：
Gravel, RA
中科院分区：
文献类型：
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作者：
Phaneuf, D;Wakamatsu, N;Gravel, RA
我们通过分别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Herb（β亚基）基因，建立了人类Tay-Sachs和Sandhoff疾病的小鼠模型。两种突变小鼠在大脑中积累G（M2）神经节苷脂，在Herb -/-小鼠中更是如此，后者还积累糖脂G（A2）Hexa -/- 小鼠没有明显的行为或神经缺陷，而 Herb -/- 小鼠则出现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。 Herb -/- 但 Hexa -/- 小鼠的脊髓轴突大量耗竭，这是 G(M2) 神经元储存的明显结果。我们认为，Hexa -/- 小鼠通过唾液酸酶和 β-己糖胺酶 B 的联合作用，通过 G(A2) (asialo-G(M2)) 部分分解代谢累积的 G(M2)，从而逃避疾病。
We have generated mouse models of human Tay-Sachs and Sandhoff diseases by targeted disruption of the Hexa (alpha subunit) or Herb (beta subunit) genes, respectively, encoding lysosomal beta-hexosaminidase A (structure, alpha) and B (structure, beta beta) Both mutant mice accumulate G(M2) ganglioside in brain, much more so in Herb -/- mice, and the latter also accumulate glycolipid G(A2) Hexa -/- mice suffer no obvious behavioral or neurological deficit, while Herb -/- mice develop a fatal neurodegenerative disease, with spasticity, muscle weakness, rigidity, tremor and ataxia. The Herb -/- but not the Hexa -/- mice have massive depletion of spinal cord axons as an apparent consequence of neuronal storage of G(M2) We propose that Hexa -/- mice escape disease through partial catabolism of accumulated G(M2) via G(A2) (asialo-G(M2)) through the combined action of sialidase and beta-hexosaminidase B.