Peptide TFP5/TP5 derived from Cdk5 activator P35 provides neuroprotection in the MPTP model of Parkinson's disease.
Peptide TFP5/TP5 derived from Cdk5 activator P35 provides neuroprotection in the MPTP model of Parkinson's disease.
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DOI：
10.1091/mbc.e15-06-0415
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发表时间：
2015-12-01
影响因子：
3.3
通讯作者：
Pant HC
中科院分区：
文献类型：
--
作者：
Binukumar BK;Shukla V;Amin ND;Grant P;Bhaskar M;Skuntz S;Steiner J;Pant HC
TFP 5/TP 5在帕金森病（PD）小鼠模型中挽救由MPTP诱导的多巴胺能神经变性TFP 5/TP 5肽的神经保护作用还与神经炎症和细胞凋亡的显著减少相关。TFP 5/TP 5肽对Cdk 5/p25的选择性抑制将激酶鉴定为减少PD神经变性的潜在靶点。帕金森病（PD）是一种慢性神经退行性疾病，其特征在于黑质中多巴胺神经元的损失、纹状体多巴胺水平降低以及随之发生的锥体外系运动功能障碍。最近的证据表明，细胞周期蛋白依赖性激酶5（Cdk 5）在几种神经退行性疾病中被不适当地激活，包括PD。迄今为止，特异性抑制Cdk 5活性亢进的策略在不影响正常Cdk 5活性的情况下尚未成功。以前我们报道过TFP 5肽在阿尔茨海默病动物模型中具有神经保护作用。在这里，我们表明，TFP 5/TP 5在体内和体外选择性抑制Cdk 5/p25超活化拯救黑质纹状体多巴胺能神经变性诱导的1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP/MPP+）在PD小鼠模型。TP 5肽治疗还阻断纹状体中的多巴胺耗竭，并改善MPTP给药后的步态功能障碍。TFP 5/TP 5肽的神经保护作用还与神经炎症和细胞凋亡的显著减少相关。在这里，我们展示了TFP 5/TP 5肽对Cdk 5/p25激酶过度激活的选择性抑制，这将激酶鉴定为减少帕金森病神经变性的潜在治疗靶点。
TFP5/TP5 rescues dopaminergic neurodegeneration induced by MPTP in a mouse model of Parkinson’s disease (PD). The neuroprotective effect of TFP5/TP5 peptide is also associated with marked reduction in neuroinflammation and apoptosis. Selective inhibition of Cdk5/p25 by TFP5/TP5 peptide identifies the kinase as a potential target to reduce neurodegeneration in PD. Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. Recent evidence indicates that cyclin-dependent kinase 5 (Cdk5) is inappropriately activated in several neurodegenerative conditions, including PD. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Previously we reported that TFP5 peptide has neuroprotective effects in animal models of Alzheimer’s disease. Here we show that TFP5/TP5 selective inhibition of Cdk5/p25 hyperactivation in vivo and in vitro rescues nigrostriatal dopaminergic neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) in a mouse model of PD. TP5 peptide treatment also blocked dopamine depletion in the striatum and improved gait dysfunction after MPTP administration. The neuroprotective effect of TFP5/TP5 peptide is also associated with marked reduction in neuroinflammation and apoptosis. Here we show selective inhibition of Cdk5/p25 hyperactivation by TFP5/TP5 peptide, which identifies the kinase as a potential therapeutic target to reduce neurodegeneration in Parkinson’s disease.