siRNA-based inhibition specific for mutant SOD1 with single nucleotide alternation in familial ALS, compared with ribozyme and DNA enzyme
siRNA-based inhibition specific for mutant SOD1 with single nucleotide alternation in familial ALS, compared with ribozyme and DNA enzyme
复制标题
DOI：
10.1016/j.bbrc.2003.12.098
复制
发表时间：
2004-01-30
影响因子：
3.1
通讯作者：
Mizusawa, H
中科院分区：
文献类型：
--
作者：
Yokota, T;Miyagishi, M;Mizusawa, H
在家族性肌萎缩侧索硬化症（ALS）等常染色体显性遗传疾病中，SOD 1基因的错义点突变可能通过获得不利的遗传特性而导致疾病的发生。预期这种突变蛋白表达的减少会改善疾病表型。21-nt RNA的双链体（Duplex of 21-nt RNA，siRNA）是近年来出现的一种有效的基因沉默工具，但与核酶和DNA酶相比，siRNA的序列特异性和有效性还没有得到充分的研究。我们可以制造甚至识别单核苷酸改变的siRNA，并选择性地抑制G93 A SOD 1表达，使野生型SOD 1保持完整。在哺乳动物细胞中，siRNA比核酶或DNA酶更有效地抑制突变SOD 1的表达。此外，这些siRNA可以抑制由突变SOD Is过表达诱导的Neuro 2a细胞死亡，并伴有蛋白酶体抑制应激。我们的研究结果支持利用基于siRNA的基因治疗具有突变SOD 1的家族性ALS的可行性。(C)2003年爱思唯尔公司All rights reserved.
In many of autosomal dominant diseases such as familial amyotrophic lateral sclerosis (ALS) with SOD1 mutation, a missense point mutation may induce the disease by its gain of adverse property. Reduction of such a mutant protein expression is expected to improve the disease phenotype. Duplex of 21-nt RNA, known as siRNA, has recently emerged as a powerful tool to silence gene, but the sequence specificity and efficacies have not been fully studied in comparison with ribozyme and DNA enzyme. We could make the siRNA which recognized even a single nucleotide alternation and selectively suppress G93A SOD1 expression leaving wild-type SOD1 intact. In mammalian cells, the siRNA much more efficiently suppressed the expression of mutant SOD1 than ribozyme or DNA enzyme. Furthermore, these siRNAs could suppress cell death of Neuro2a induced by over-expression of mutant SOD Is with stress of proteasome inhibition. Our results support the feasibility of utilizing siRNA-based gene therapy of familial ALS with mutant SOD1. (C) 2003 Elsevier Inc. All rights reserved.