Roscovitine, a Cyclin-Dependent Kinase-5 Inhibitor, Decreases Phosphorylated Tau Formation and Death of Retinal Ganglion Cells of Rats after Optic Nerve Crush.
Roscovitine, a Cyclin-Dependent Kinase-5 Inhibitor, Decreases Phosphorylated Tau Formation and Death of Retinal Ganglion Cells of Rats after Optic Nerve Crush.
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DOI：
10.3390/ijms22158096
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发表时间：
2021-07-28
影响因子：
5.6
通讯作者：
Oku H
中科院分区：
文献类型：
--
作者：
Hirokawa T;Horie T;Fukiyama Y;Mimura M;Takai S;Kida T;Oku H
Tau病是以错误折叠的tau蛋白的异常代谢为特征的神经退行性疾病，是进行性的。视神经损伤后，视网膜神经节细胞(RGC)中存在tau的病理性磷酸化。细胞周期蛋白依赖性激酶-5(CDK5)引起tau蛋白过度磷酸化。为确定CDK5在视网膜退行性变中的作用，在视神经夹闭(ONC)后，玻璃体内注射CDK5抑制剂ROSCOVITE。免疫印迹法检测视网膜神经节细胞中磷酸化tau蛋白、钙蛋白酶-1和裂解α-fodrin的表达水平；免疫组织化学方法检测CDK5激活剂P35/P25在视网膜神经节细胞中的表达。结果表明，罗斯科维汀使磷酸化tau的水平降低了3.5-1.6倍。在第3天，Calain-1(2.1倍)和裂解的α-fodrin(1.5倍)增加，这表明Calain信号通路被激活。P35/P25在Tuj-1染色较弱的视网膜节细胞中积聚。抑制钙蛋白酶也减少了磷酸化tau的增加。培养第7天，RGCs数量由假手术组的2191±178个/mm2降至1216±122个/mm2，罗索维汀维持在1622±130个/mm2的水平。我们的结论是，钙蛋白酶介导的CDK5激活与tau的病理性磷酸化有关。
Tauopathies are neurodegenerative diseases characterized by abnormal metabolism of misfolded tau proteins and are progressive. Pathological phosphorylation of tau occurs in the retinal ganglion cells (RGCs) after optic nerve injuries. Cyclin-dependent kinase-5 (Cdk5) causes hyperphosphorylation of tau. To determine the roles played by Cdk5 in retinal degeneration, roscovitine, a Cdk5 inhibitor, was injected intravitreally after optic nerve crush (ONC). The neuroprotective effect of roscovitine was determined by the number of Tuj-1-stained RGCs on day 7. The change in the levels of phosphorylated tau, calpain-1, and cleaved α-fodrin was determined by immunoblots on day 3. The expression of P35/P25, a Cdk5 activator, in the RGCs was determined by immunohistochemistry. The results showed that roscovitine reduced the level of phosphorylated tau by 3.5- to 1.6-fold. Calpain-1 (2.1-fold) and cleaved α-fodrin (1.5-fold) were increased on day 3, suggesting that the calpain signaling pathway was activated. P35/P25 was accumulated in the RGCs that were poorly stained by Tuj-1. Calpain inhibition also reduced the increase in phosphorylated tau. The number of RGCs decreased from 2191 ± 178 (sham) to 1216 ± 122 cells/mm2 on day 7, and roscovitine preserved the level at 1622 ± 130 cells/mm2. We conclude that the calpain-mediated activation of Cdk5 is associated with the pathologic phosphorylation of tau.
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DOI：
10.1111/j.1432-1033.1997.t01-2-00527.x
发表时间：
1997-01-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Meijer, L;Borgne, A;Moulinoux, JP
通讯作者：
Moulinoux, JP
影响因子：
3.7
作者：
Menn B;Bach S;Blevins TL;Campbell M;Meijer L;Timsit S
通讯作者：
Timsit S
Calpain/p35-p25/Cdk5/NMDAR 信号通路参与谷氨酸诱导的培养大鼠视网膜神经元神经毒性
影响因子：
3.7
作者：
Miao Y;Dong LD;Chen J;Hu XC;Yang XL;Wang Z
通讯作者：
Wang Z
影响因子：
2
作者：
Dureau, P;Bonnel, S;Abitbol, M
通讯作者：
Abitbol, M
影响因子：
4.6
作者：
Maekawa S;Sato K;Fujita K;Daigaku R;Tawarayama H;Murayama N;Moritoh S;Yabana T;Shiga Y;Omodaka K;Maruyama K;Nishiguchi KM;Nakazawa T
通讯作者：
Nakazawa T