title: Enhanced Proteostasis in Post-ischemic Stroke Mouse Brains by Ubiquilin-1 Promotes Functional Recovery.
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.
authors.affiliation: Division of Basic Biomedical Sciences and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, SD, 57069, USA.
authors.forename: Yanying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Basic Biomedical Sciences and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, SD, 57069, USA.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Qiao
authors.affiliation: Division of Basic Biomedical Sciences and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, SD, 57069, USA. Hongmin.Wang@usd.edu.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000008:administration & dosage / Q000096:biosynthesis*; D000818:Animals; D000071183:Autophagy-Related Proteins; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D007276:Injections, Intraventricular; D016086:Lentivirus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000074702:Proteostasis / Q000187:drug effects / Q000502:physiology*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000071183:Autophagy-Related Proteins; C538987:UBQLN1 protein, mouse
keywords: Brain ischemia; Neuroprotection; Protein aggregates; Reperfusion; Stroke; Ubiquilin-1