Enhanced proteostasis in post-ischemic stroke mouse brains by ubiquilin-1 promotes functional recovery

Y Liu, F Qiao, H Wang - Cellular and molecular neurobiology, 2017 - Springer
Y Liu, F Qiao, H Wang
Cellular and molecular neurobiology, 2017Springer
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 …
Abstract
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.
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