Modification of ubiquitin-C-terminal hydrolase-L1 by cyclopentenone prostaglandins exacerbates hypoxic injury.
Modification of ubiquitin-C-terminal hydrolase-L1 by cyclopentenone prostaglandins exacerbates hypoxic injury.
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DOI：
10.1016/j.nbd.2010.09.020
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发表时间：
2011-02
影响因子：
6.1
通讯作者：
Graham, Steven H.
中科院分区：
文献类型：
--
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.
关键词：
环戊烯酮前列腺素，如15-脱氧前列腺素12，14-前列腺素J2(15-deoxy-Δ12，14-prostaglandin J2，15d-PGJ2)，是一种活性前列腺素代谢产物，具有多种生物学效应，可能在神经系统疾病的发病机制中起重要作用。泛素C末端水解酶L1(UCH-L1)是一种脑特异性脱泛素酶，其功能异常与神经退行性疾病有关。我们报道了短暂性局灶性脑缺血后大鼠脑内四极杆细胞质谱仪(MS)检测到的[15d-PGJ2]升高，15d-PGJ2治疗可诱导泛素蛋白积聚，加重常氧和低氧原代神经元的细胞死亡。15D-PGJ2共价修饰UCH-L1并抑制其水解酶活性。药物抑制UCH-L1加重缺氧性神经元死亡，而TAT-UCH-L1融合蛋白转导保护神经元免受缺氧。这些研究表明，UCH-L1功能在缺氧性神经元死亡中起重要作用，卒中后CyPG的过量产生可能通过对UCH-L1的修饰和抑制而加重缺血性损伤。
Cyclopentenone prostaglandins (CyPGs), such as 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), are active prostaglandin metabolites exerting a variety of biological effects that may be important in the pathogenesis of neurological diseases. Ubiquitin-C-terminal hydrolase L1 (UCH-L1) is a brain specific deubiquitinating enzyme whose aberrant function has been linked to neurodegenerative disorders. We report that [15d-PGJ2] detected by quadrapole mass spectrometry (MS) increases in rat brain after temporary focal ischemia, and that treatment with 15d-PGJ2 induces accumulation of ubiquitinated proteins and exacerbates cell death in normoxic and hypoxic primary neurons. 15d-PGJ2 covalently modifies UCH-L1 and inhibits its hydrolase activity. Pharmacologic inhibition of UCH-L1 exacerbates hypoxic neuronal death while transduction with a TAT-UCH-L1 fusion protein protects neurons from hypoxia. These studies indicate UCH-L1 function is important in hypoxic neuronal death and excessive production of CyPGs after stroke may exacerbate ischemic injury by modification and inhibition of UCH-L1.
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影响因子：
3.3
作者：
Liu, CL;Ge, P;Hu, BR
通讯作者：
Hu, BR
影响因子：
3.4
作者：
García-Bueno, B;Madrigal, JLM;Leza, JC
通讯作者：
Leza, JC
DOI：
10.1177/1073858408327809
发表时间：
2009-06
期刊：
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
影响因子：
--
作者：
Meller R
通讯作者：
Meller R
影响因子：
4.8
作者：
Choi, J;Levey, AI;Li, L
通讯作者：
Li, L
影响因子：
4.2
作者：
Li, ZM;Jansen, M;Figueiredo-Pereira, ME
通讯作者：
Figueiredo-Pereira, ME