Stroke Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
PLoS One. 2011;6(10):e25852. doi: 10.1371/journal.pone.0025852. Epub 2011 Oct 7.
We have previously shown that a massive increase in global SUMOylation occurs during torpor in ground squirrels, and that overexpression of Ubc9 and/or SUMO-1 in cell lines and cortical neurons protects against oxygen and glucose deprivation. To examine whether increased global SUMOylation protects against ischemic brain damage, we have generated transgenic mice in which Ubc9 is expressed strongly in all tissues under the chicken β-actin promoter. Ubc9 expression levels in 10 founder lines ranged from 2 to 30 times the endogenous level, and lines that expressed Ubc9 at modestly increased levels showed robust resistance to brain ischemia compared to wild type mice. The infarction size was inversely correlated with the Ubc9 expression levels for up to five times the endogenous level. Although further increases showed no additional benefit, the Ubc9 expression level was highly correlated with global SUMO-1 conjugation levels (and SUMO-2,3 levels to a lesser extent) up to a five-fold Ubc9 increase. Most importantly, there were striking reciprocal relationships between SUMO-1 (and SUMO-2,3) conjugation levels and cerebral infarction volumes among all tested animals, suggesting that the limit in cytoprotection by global SUMOylation remains undefined. These results support efforts to further augment global protein SUMOylation in brain ischemia.
我们之前已经表明，在土拨鼠的冬眠期间，全球 SUMOylation 大量增加，并且细胞系和皮质神经元中 Ubc9 和/或 SUMO-1 的过表达可以防止缺氧和葡萄糖剥夺。为了研究增加的全局 SUMOylation 是否可以防止脑缺血损伤，我们已经生成了转 Ubc9 基因的小鼠，在鸡β-肌动蛋白启动子的控制下，Ubc9 在所有组织中都强烈表达。在 10 个初始系中，Ubc9 的表达水平比内源性水平高 2 到 30 倍，并且表达 Ubc9 适度增加的系与野生型小鼠相比对脑缺血具有更强的抗性。梗塞面积与 Ubc9 的表达水平呈反比，最高可达内源性水平的五倍。尽管进一步增加没有带来额外的好处，但 Ubc9 的表达水平与全球 SUMO-1 缀合水平（以及 SUMO-2,3 水平的程度较小）高度相关，最高可达 Ubc9 增加的五倍。最重要的是，在所有测试的动物中，SUMO-1（和 SUMO-2,3）缀合水平与脑梗死体积之间存在惊人的相互关系，这表明全局 SUMOylation 的细胞保护限制尚不清楚。这些结果支持进一步增加脑缺血中全局蛋白 SUMOylation 的努力。
