Mutation of a Ubiquitin Carboxy Terminal Hydrolase L1 Lipid Binding Site Alleviates Cell Death, Axonal Injury, and Behavioral Deficits After Traumatic Brain Injury in Mice.
Mutation of a Ubiquitin Carboxy Terminal Hydrolase L1 Lipid Binding Site Alleviates Cell Death, Axonal Injury, and Behavioral Deficits After Traumatic Brain Injury in Mice.
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DOI：
10.1016/j.neuroscience.2021.09.001
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发表时间：
2021-11-01
期刊：
影响因子：
3.3
通讯作者：
Graham SH
中科院分区：
文献类型：
--
作者：
Mi Z;Liu H;Rose ME;Ma J;Reay DP;Ma X;Henchir JJ;Dixon CE;Graham SH
泛素羧基末端水解酶L1 （UCHL1）是一种在神经元中高表达的蛋白，可能在创伤性脑损伤（TBI）后神经元、轴突完整性和运动功能的泛素蛋白酶体途径中发挥重要作用。反应性脂质与UCHL1的半胱氨酸152结合导致该酶的展开、聚集和失活。为了测试这种机制在TBI中的作用，在152位点携带半胱氨酸到丙氨酸突变的小鼠（C152A小鼠）使UCHL1抵抗活性脂质的失活，并将其置于TBI的受控皮质冲击模型（CCI）中，并与野生型（WT）对照进行比较。免疫印迹法检测脑损伤后蛋白泛素化和自噬通路标志物的激活变化。采用组织病理学和抗淀粉样蛋白前体（APP）免疫组化检测细胞死亡和轴突损伤。行为结果通过平衡木和Morris水迷宫测试确定。与WT对照组相比，CCI后C152A小鼠泛素化蛋白的积累减少，自噬标志物Beclin-1和LC3B的激活减少，异常轴突数量减少，CA1细胞死亡减少，运动和认知功能改善；未观察到备用组织体积的显著变化。这些结果表明，脂质底物与UCHL1的半胱氨酸152的结合在TBI后损伤和恢复的发病机制中很重要，可能是未来治疗方法的新靶点。
Ubiquitin carboxy terminal hydrolase L1 (UCHL1) is a protein highly expressed in neurons that may play important roles in the ubiquitin proteasome pathway in neurons, axonal integrity, and motor function after traumatic brain injury (TBI). Binding of reactive lipid species to cysteine 152 of UCHL1 results in unfolding, aggregation, and inactivation of the enzyme. To test the role of this mechanism in TBI, mice bearing a cysteine to alanine mutation at site 152 (C152A mice) that renders UCHL1 resistant to inactivation by reactive lipids were subjected to the controlled cortical impact model (CCI) of TBI and compared to wild type (WT) controls. Alterations in protein ubiquitination and activation of autophagy pathway markers in traumatized brain were detected by immunoblotting. Cell death and axonal injury were determined by histological assessment and anti-amyloid precursor protein (APP) immunohistochemistry. Behavioral outcomes were determined using the beam balance and Morris water maze tests. C152A mice had reduced accumulation of ubiquitinated proteins, decreased activation of the autophagy markers Beclin-1 and LC3B, a decreased number of abnormal axons, decreased CA1 cell death, and improved motor and cognitive function compared to WT controls after CCI; no significant change in spared tissue volume was observed. These results suggest that binding of lipid substrates to cysteine 152 of UCHL1 is important in the pathogenesis of injury and recovery after TBI and may be a novel target for future therapeutic approaches.
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影响因子：
4.8
作者：
Figueiredo-Pereira ME;Rockwell P;Schmidt-Glenewinkel T;Serrano P
通讯作者：
Serrano P
DOI：
10.1093/cercor/bhu318
发表时间：
2015-11
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
--
作者：
Jara JH;Genç B;Cox GA;Bohn MC;Roos RP;Macklis JD;Ulupınar E;Özdinler PH
通讯作者：
Özdinler PH
影响因子：
3.6
作者：
Hickey, Robert W.;Adelson, P. David;Graham, Steven H.
通讯作者：
Graham, Steven H.
影响因子：
2.6
作者：
Jara, Javier H.;Frank, Dominic D.;Oezdinler, P. Hande
通讯作者：
Oezdinler, P. Hande
影响因子：
5.3
作者：
Hu, BR;Martone, ME;Liu, CL
通讯作者：
Liu, CL