Abolishing UCHL1's hydrolase activity exacerbates TBI-induced axonal injury and neuronal death in mice.
Abolishing UCHL1's hydrolase activity exacerbates TBI-induced axonal injury and neuronal death in mice.
复制标题
废除UCHL1的水解酶活性加剧了小鼠TBI诱导的轴突损伤和神经元死亡。
DOI：
10.1016/j.expneurol.2020.113524
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发表时间：
2021-03
影响因子：
5.3
通讯作者：
Graham SH
中科院分区：
文献类型：
--
作者：
Mi Z;Liu H;Rose ME;Ma X;Reay DP;Ma J;Henchir J;Dixon CE;Graham SH
泛素（Ub）C末端水解酶L1（UCHL 1）是一种多功能蛋白质，在整个大脑的神经元中以高水平表达。UCHL 1缺失与小鼠轴突变性、进行性感觉运动共济失调和过早死亡相关。UCHL 1被认为在神经退行性疾病的发病机制和神经元损伤后的恢复中发挥作用。UCHL 1从多聚泛素化（poly-Ub）蛋白水解Ub，但也可以连接Ub以选择神经元蛋白，并与细胞骨架蛋白相互作用。这些和其他机制已被假设为UCHL 1在神经变性和对脑损伤的反应中的作用的基础。构建了一个UCHL 1敲入小鼠含有C90 A突变（C90 A）缺乏水解酶活性。C90 A小鼠没有出现感觉和运动缺陷、薄束核和束变性或UCHL 1缺陷小鼠中所见的过早死亡。对C90 A和野生型（WT）小鼠进行创伤性脑损伤（TBI）的受控皮质撞击（CCI）模型，并评估细胞死亡、轴突损伤和行为结果。与WT对照相比，C90 A小鼠在CCI后表现出减少的备用组织体积、更大的CA 1海马神经元损失和更大的轴突损伤，如使用抗淀粉样前体蛋白（APP）抗体和抗非磷酸化神经丝H（SMI-32）抗体免疫组织化学检测的。与WT对照组相比，C90 A小鼠在CCI后Poly-Ub蛋白和Beclin-1升高。使用平衡木测试评估的前庭运动缺陷在WT小鼠中在CCI后第5天得到解决，但在C90 A小鼠中则没有。这些结果表明，UCHL 1的水解酶活性不能解释在不表达全长UCHL 1的小鼠中观察到的进行性神经变性和过早死亡。UCHL 1的水解酶活性有助于泛素蛋白酶体途径（UPP）的功能，改善自噬的激活，并改善CCI后的运动恢复。因此，UCHL 1水解酶活性在TBI后的急性损伤反应中起重要作用。
Ubiquitin (Ub) C-terminal hydrolase L1 (UCHL1) is a multifunctional protein that is expressed in neurons throughout brain at high levels. UCHL1 deletion is associated with axonal degeneration, progressive sensory motor ataxia, and premature death in mice. UCHL1 has been hypothesized to play a role in the pathogenesis of neurodegenerative diseases and recovery after neuronal injury. UCHL1 hydrolyzes Ub from polyubiquitinated (poly-Ub) proteins, but also may ligate Ub to select neuronal proteins, and interacts with cytoskeletal proteins. These and other mechanisms have been hypothesized to underlie UCHL1’s role in neurodegeneration and response to brain injury. A UCHL1 knockin mouse containing a C90A mutation (C90A) devoid of hydrolase activity was constructed. The C90A mouse did not develop the sensory and motor deficits, degeneration of the gracile nucleus and tract, or premature death as seen in UCHL1 deficient mice. C90A and wild type (WT) mice were subjected to the controlled cortical impact (CCI) model of traumatic brain injury (TBI), and cell death, axonal injury and behavioral outcome were assessed. C90A mice exhibited decreased spared tissue volume, greater loss of CA1 hippocampal neurons and greater axonal injury as detected using anti-amyloid precursor protein (APP) antibody and anti- non-phosphorylated neurofilament H (SMI-32) antibody immunohistochemistry after CCI than WT controls. Poly-Ub proteins and Beclin-1 were elevated after CCI in C90A mice compared to WT controls. Vestibular motor deficits assessed using the beam balance test resolved by day 5 after CCI in WT mice but not in C90A mice. These results suggest that the hydrolase activity of UCHL1 does not account for the progressive neurodegeneration and premature death seen in mice that do not express full length UCHL1. The hydrolase activity of UCHL1 contributes to the function of the ubiquitin proteasome pathway (UPP), ameliorates activation of autophagy, and improves motor recovery after CCI. Thus, UCHL1 hydrolase activity plays an important role in acute injury response after TBI.
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影响因子：
9
作者：
Liu H;Li W;Rose ME;Hickey RW;Chen J;Uechi GT;Balasubramani M;Day BW;Patel KV;Graham SH
通讯作者：
Graham SH
影响因子：
6.1
作者：
Liu, Hao;Li, Wenjin;Ahmad, Muzamil;Miller, Tricia M.;Rose, Marie E.;Poloyac, Samuel M.;Uechi, Guy;Balasubramani, Manimalha;Hickey, Robert W.;Graham, Steven H.
通讯作者：
Graham, Steven H.
泛素编辑酶UCH L1和微管动力学：有丝分裂的影响。
DOI：
10.4161/cc.9.5.10934
发表时间：
2010-03-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Bheda A;Gullapalli A;Caplow M;Pagano JS;Shackelford J
通讯作者：
Shackelford J
影响因子：
4.2
作者：
Kunz, T;Marklund, N;Oliw, EH
通讯作者：
Oliw, EH
影响因子：
4.1
作者：
DIXON, CE;LYETH, BG;HAYES, RL
通讯作者：
HAYES, RL