Abolishing UCHL1's hydrolase activity exacerbates ischemia-induced axonal injury and functional deficits in mice.

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Zhiping Mi, Nadya Povysheva, Marie E Rose, Jie Ma, Dennis J Zeh, Nikitha Harikumar, Mohammad Iqbal H Bhuiyan, Steven H Graham
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引用次数: 0

Abstract

Ubiquitin C-terminal hydrolase L1 (UCHL1) is a neuronal protein important in maintaining axonal integrity and motor function and may be important in the pathogenesis of many neurological disorders. UCHL1 may ameliorate acute injury and improve recovery after cerebral ischemia. In the current study, the hypothesis that UCHL1's hydrolase activity underlies its effect in maintaining axonal integrity and function is tested after ischemic injury. Hydrolase activity was inhibited by treatment with a UCHL1 hydrolase inhibitor or by employing knockin mice bearing a mutation in the hydrolase active site (C90A). Ischemic injury was induced by oxygen-glucose deprivation (OGD) in brain slice preparations and by transient middle cerebral artery occlusion (tMCAO) surgery in mice. Hydrolase activity inhibition increased restoration time and decreased the amplitude of evoked axonal responses in the corpus callosum after OGD. Mutation of the hydrolase active site exacerbated white matter injury as detected by SMI32 immunohistochemistry, and motor deficits as detected by beam balance and cylinder testing after tMCAO. These results demonstrate that UCHL1 hydrolase activity ameliorates white matter injury and functional deficits after acute ischemic injury and support the hypothesis that UCHL1 activity plays a significant role in preserving white matter integrity and recovery of function after cerebral ischemia.

消除 UCHL1 的水解酶活性会加剧缺血诱导的小鼠轴突损伤和功能障碍。
泛素 C 端水解酶 L1(UCHL1)是一种神经元蛋白,对维持轴突完整性和运动功能非常重要,可能与许多神经系统疾病的发病机制有关。UCHL1 可减轻急性损伤并改善脑缺血后的恢复。本研究对 UCHL1 的水解酶活性是其维持轴突完整性和功能的基础这一假设进行了测试。通过使用 UCHL1 水解酶抑制剂或使用水解酶活性位点突变(C90A)的基因敲除小鼠来抑制水解酶活性。脑片制备过程中的氧-葡萄糖剥夺(OGD)和小鼠一过性大脑中动脉闭塞(tMCAO)手术都会诱发缺血性损伤。抑制水解酶活性可延长OGD后胼胝体的恢复时间并降低诱发轴突反应的幅度。水解酶活性位点的突变加剧了SMI32免疫组化检测到的白质损伤,以及tMCAO后梁平衡和圆柱体测试检测到的运动障碍。这些结果表明,UCHL1水解酶活性可改善急性缺血性损伤后的白质损伤和功能障碍,并支持UCHL1活性在保护白质完整性和脑缺血后功能恢复方面发挥重要作用的假设。
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来源期刊
Journal of Cerebral Blood Flow and Metabolism
Journal of Cerebral Blood Flow and Metabolism 医学-内分泌学与代谢
CiteScore
12.00
自引率
4.80%
发文量
300
审稿时长
3 months
期刊介绍: JCBFM is the official journal of the International Society for Cerebral Blood Flow & Metabolism, which is committed to publishing high quality, independently peer-reviewed research and review material. JCBFM stands at the interface between basic and clinical neurovascular research, and features timely and relevant research highlighting experimental, theoretical, and clinical aspects of brain circulation, metabolism and imaging. The journal is relevant to any physician or scientist with an interest in brain function, cerebrovascular disease, cerebral vascular regulation and brain metabolism, including neurologists, neurochemists, physiologists, pharmacologists, anesthesiologists, neuroradiologists, neurosurgeons, neuropathologists and neuroscientists.
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