Selective knockdown of mutant SOD1 in Schwann cells ameliorates disease in G85R mutant SOD1 transgenic mice.
Selective knockdown of mutant SOD1 in Schwann cells ameliorates disease in G85R mutant SOD1 transgenic mice.
复制标题
施万细胞中选择性敲除突变型 SOD1 可改善 G85R 突变型 SOD1 转基因小鼠的疾病。
DOI：
10.1016/j.nbd.2012.05.014
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发表时间：
2012
影响因子：
6.1
通讯作者：
Roos,RaymondP
中科院分区：
文献类型：
--
作者：
Wang,Lijun;Pytel,Peter;Feltri,MLaura;Wrabetz,Lawrence;Roos,RaymondP
具有完全歧化酶活性（例如 G37R）以及无歧化酶活性（例如 G85R）的 1 型超氧化物歧化酶 (mtSOD1) 突变体会导致家族性肌萎缩侧索硬化症 (FALS)，表明 mtSOD1 诱导的 FALS 是由毒性而不是 SOD1 酶活性丧失所致。尽管如此，目前尚不清楚 mtSOD1 歧化酶活性是否会影响疾病。先前的一项研究表明，Cre 介导的 G37R 转基因小鼠雪旺细胞 (SC) 中 G37R 表达的敲低可缩短疾病晚期和生存期。这些结果表明，SCs 中表达的 G37R 的神经保护作用大于其毒性，可能是因为其歧化酶活性抵消了活性氧 (ROS)。为了进一步研究这一点，我们通过将 G85Rfloxmice 与髓鞘蛋白零 (P0):Cre 小鼠杂交来敲低 SC 中的 G85R，后者在 SC 中表达 Cre 重组酶。 G85R 小鼠 SC 中 G85R 的敲低可延迟疾病发作并延长生存期，表明 SC 中 G85R 的表达具有神经毒性。这些结果表明歧化酶活性与非活性 mtSOD1 对疾病的影响存在差异，表明 mtSOD1 功能的丧失和增强都会影响 FALS 发病机制。结果表明，mtSOD1 诱导的 FALS 治疗可能需要根据目标细胞类型和涉及的特定 mtSOD1 进行调整。
Mutants of superoxide dismutase type 1 (mtSOD1) that have full dismutase activity (e.g., G37R) as well as none (e.g., G85R) cause familial amyotrophic lateral sclerosis (FALS), indicating that mtSOD1-induced FALS results from a toxicity rather than loss in SOD1 enzymatic activity. Still, it has remained unclear whether mtSOD1 dismutase activity can influence disease. A previous study demonstrated that Cre-mediated knockdown of G37R expression in Schwann cells (SCs) of G37R transgenic mice shortened the late phase of disease and survival. These results suggested that the neuroprotective effect of G37R expressed in SCs was greater than its toxicity, presumably because its dismutase activity counteracted reactive oxygen species (ROS). In order to further investigate this, we knocked down G85R in SCs by crossing G85Rfloxmice with myelin-protein-zero (P0):Cre mice, which express Cre recombinase in SCs. Knockdown of G85R in SCs of G85R mice delayed disease onset and extended survival indicating that G85R expression in SCs is neurotoxic. These results demonstrate differences in the effect on disease of dismutase active vs. inactive mtSOD1 suggesting that both a loss as well as gain in function of mtSOD1 influence FALS pathogenesis. The results suggest that mtSOD1-induced FALS treatment may have to be adjusted depending on the cell type targeted and particular mtSOD1 involved.