Institute of Biochemistry I, Jena University Hospital-Friedrich Schiller University Jena, Jena, Germany.
Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
PLoS Biol. 2021 Dec 13;19(12):e3001399. doi: 10.1371/journal.pbio.3001399. eCollection 2021 Dec.
Ischemic stroke is a major cause of death and long-term disability. We demonstrate that middle cerebral artery occlusion (MCAO) in mice leads to a strong decline in dendritic arborization of penumbral neurons. These defects were subsequently repaired by an ipsilateral recovery process requiring the actin nucleator Cobl. Ischemic stroke and excitotoxicity, caused by calpain-mediated proteolysis, significantly reduced Cobl levels. In an apparently unique manner among excitotoxicity-affected proteins, this Cobl decline was rapidly restored by increased mRNA expression and Cobl then played a pivotal role in poststroke dendritic arbor repair in peri-infarct areas. In Cobl knockout (KO) mice, the dendritic repair window determined to span day 2 to 4 poststroke in wild-type (WT) strikingly passed without any dendritic regrowth. Instead, Cobl KO penumbral neurons of the primary motor cortex continued to show the dendritic impairments caused by stroke. Our results thereby highlight a powerful poststroke recovery process and identified causal molecular mechanisms critical during poststroke repair.
缺血性中风是死亡和长期残疾的主要原因。我们证明，小鼠大脑中动脉闭塞（MCAO）导致半影区神经元树突分支明显减少。随后，这些缺陷通过同侧的恢复过程得到修复，该过程需要肌动蛋白成核因子 Cobl。缺血性中风和兴奋性毒性会导致钙蛋白酶介导的蛋白水解，从而显著降低 Cobl 水平。在受兴奋性毒性影响的蛋白中，Cobl 的这种下降以一种明显独特的方式被快速地通过增加 mRNA 表达来恢复，Cobl 在梗死后的树突修复中发挥了关键作用，主要在梗死周围区域。在 Cobl 敲除（KO）小鼠中，在野生型（WT）中确定跨越中风后第 2 至 4 天的树突修复窗口明显没有任何树突生长。相反，Cobl KO 初级运动皮层的半影神经元继续显示出中风引起的树突损伤。我们的结果因此强调了一种强大的中风后恢复过程，并确定了中风后修复过程中的关键因果分子机制。
