Division of Basic Biomedical Sciences and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, SD, 57069, USA.
Cell Mol Neurobiol. 2017 Oct;37(7):1325-1329. doi: 10.1007/s10571-016-0451-3. Epub 2016 Dec 7.
Stroke is pathologically associated with oxidative stress, protein damage, and neuronal loss. We previously reported that overexpression of a ubiquitin-like protein, ubiquilin-1 (Ubqln), protects neurons against ischemia-caused brain injury, while knockout of the gene exacerbates cerebral ischemia-caused neuronal damage and delays functional recovery. Although these observations indicate that Ubqln is a potential therapeutic target, transgenic manipulation-caused overexpression of Ubqln occurs before the event of ischemic stroke, and it remains unknown whether delayed Ubqln overexpression in post-ischemic brains within a clinically relevant time frame is still beneficial. To address this question, we generated lentiviruses (LVs) either overexpressing or knocking down mouse Ubqln, and treated post-ischemic stroke mice 6 h following the middle cerebral artery occlusion with the LVs before animal behaviors were evaluated at day 1, 3, 5, and 7. Our data indicate that post-ischemic overexpression of Ubqln significantly promoted functional recovery, whereas post-ischemic downregulation of Ubqln expression delays functional recovery. To further understand the mechanisms underlying how Ubqln functions, we also isolated protein aggregates from the brains of wild-type mice or the mice overexpressing Ubqln following ischemia/reperfusion. Western blot analysis indicates that overexpression of Ubqln significantly reduced the accumulation of protein aggregates. These observations not only suggest that Ubqln is a useful candidate for therapeutic intervention for ischemic stroke but also highlight the significance of proteostasis in functional recovery following stroke.
中风与氧化应激、蛋白质损伤和神经元丧失有关。我们之前曾报道，泛素样蛋白 ubiquilin-1（Ubqln）的过表达可保护神经元免受缺血性脑损伤，而该基因的敲除则加剧了脑缺血引起的神经元损伤，并延迟了功能恢复。尽管这些观察结果表明 Ubqln 是一个有潜力的治疗靶点，但转基因操作引起的 Ubqln 过表达发生在缺血性中风之前，目前尚不清楚在临床相关时间范围内，缺血后大脑中 Ubqln 的延迟过表达是否仍然有益。为了解决这个问题，我们生成了表达或敲低小鼠 Ubqln 的慢病毒（LVs），并在大脑中动脉闭塞后 6 小时对缺血性中风小鼠进行了治疗，然后在第 1、3、5 和 7 天评估动物行为之前，用 LVs 进行了治疗。我们的数据表明，缺血后 Ubqln 的过表达显著促进了功能恢复，而 Ubqln 表达的下调则延迟了功能恢复。为了进一步了解 Ubqln 发挥作用的机制，我们还从野生型小鼠或缺血/再灌注后过表达 Ubqln 的小鼠的大脑中分离出蛋白聚集体。Western blot 分析表明，Ubqln 的过表达显著减少了蛋白聚集体的积累。这些观察结果不仅表明 Ubqln 是缺血性中风治疗干预的一个有用候选物，还强调了蛋白质稳态在中风后功能恢复中的重要性。
