Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model
Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model
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DOI：
10.1126/science.288.5464.335
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发表时间：
2000-04-14
期刊：
影响因子：
56.9
通讯作者：
Friedlander, RM
中科院分区：
文献类型：
--
作者：
Li, MW;Ona, VO;Friedlander, RM
铜/锌超氧化物歧化酶（SOD 1）基因突变产生了一种常见的肌萎缩侧索硬化症（ALS）动物模型，ALS是一种致命的神经退行性疾病。为了测试ALS的新治疗策略，我们在表达突变型人SOD 1的转基因小鼠中检测了半胱天冬酶抑制的效果，所述突变型人SOD 1在位置93处具有甘氨酸至丙氨酸的取代（mSOD 1（G93 A））。脑室内施用zVAD-fastrin，一种广泛的半胱天冬酶抑制剂。延迟疾病发作和死亡。此外，zVAD-fastin抑制caspase-1活性以及caspase-1和caspase-3 mRNA上调，为调节caspase表达的非细胞自主途径提供了证据。半胱天冬酶在转基因mSOD 1（G93 A）小鼠的神经变性中起着重要作用，这表明半胱天冬酶抑制可能在ALS中具有保护作用。
Mutations in the copper/zinc superoxide dismutase (SOD1) gene produce an animal model of familiar amyotrophic Lateral sclerosis (ALS), a fatal neurodegenerative disorder., To test a new therapeutic strategy for ALS, we examined the effect of caspase inhibition in transgenic mice expressing mutant human SOD1 with a substitution of glycine to alanine in position 93 (mSOD1(G93A)). Intracerebroventricular administration of zVAD-fmk, a broad caspase inhibitor. delays disease onset and mortality. Moreover, zVAD-fmk inhibits caspase-1 activity as well as caspase-1 and caspase-3 mRNA up-regulation, providing evidence for a non-cell-autonomous pathway regulating caspase expression. Caspases play an instrumental role in neurodegeneration in transgenic mSOD1(G93A) mice, which suggests that caspase inhibition may have a protective role in ALS.