Apoptotic cell death in mouse models of G(M2) gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases
Apoptotic cell death in mouse models of G(M2) gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases
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DOI：
10.1093/hmg/6.11.1879
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发表时间：
1997-10-01
影响因子：
3.5
通讯作者：
Gravel, RA
中科院分区：
文献类型：
--
作者：
Huang, JQ;Trasler, JM;Gravel, RA
Tay-Sachs病和Sandhoff病是常染色体隐性遗传的神经退行性疾病，由于- hexa的α亚基（Tay-Sachs病）或β亚基（Sandhoff病）突变，导致β - hexa无法分解G（M2）神经节苷脂。我们之前开发了两种疾病的小鼠模型，并表明Hexa(-/-)（tai - sachs）小鼠在至少1岁时仍无症状，而Hexb(-/-)（Sandhoff）小鼠在4-6个月大时死于一种深度神经退行性疾病。在这里，我们发现Herb（-/-）小鼠的神经元死亡与整个中枢神经系统发生的细胞凋亡有关，而Hexa（-/-）小鼠在相同年龄时很少参与。对人类泰-萨克斯病和桑德霍夫病的脑和脊髓解剖样本的研究显示，两种情况下都存在细胞凋亡，这与两种疾病的严重表达一致。我们认为神经元死亡是由非计划性凋亡引起的，暗示积累的G（M2）神经节苷脂或其衍生物触发了凋亡级联反应。
Tay-Sachs and Sandhoff diseases are autosomal recessive neurodegenerative diseases resulting from the inability to catabolize G(M2) ganglioside by beta-hexosaminidase A (Hex A) due to mutations of the alpha subunit (Tay-Sachs disease) or beta subunit (Sandhoff disease) of Hex A. Hex B (beta beta homodimer) is also defective in Sandhoff disease. We previously developed mouse models of both diseases and showed that Hexa(-/-)(Tay-Sachs) mice remain asymptomatic to at least 1 year of age while Hexb(-/-)(Sandhoff) mice succumb to a profound neurodegenerative disease by 4-6 months of age. Here we find that neuron death in Herb(-/-) mice is associated with apoptosis occurring throughout the CNS, while Hexa(-/-) mice were minimally involved at the same age. Studies of autopsy samples of brain and spinal cord from human Tay-Sachs and Sandhoff diseases revealed apoptosis in both instances, in keeping with the severe expression of both diseases. We suggest that neuron death is caused by unscheduled apoptosis, implicating accumulated G(M2) ganglioside or a derivative in triggering of the apoptotic cascade.