中国神经再生研究(英文版) ›› 2016, Vol. 11 ›› Issue (5): 698-701.doi: 10.4103/1673-5374.182681

• 综述:退行性病与再生 • 上一篇    下一篇

TFP5/TP5肽为帕金森病MPTP模型提供神经保护

  

  • 收稿日期:2016-04-15 出版日期:2016-05-20 发布日期:2016-05-20

TFP5/TP5 peptide provides neuroprotection in the MPTP model of Parkinson’s disease

Binukumar BK , Harish C. Pant*   

  1. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
  • Received:2016-04-15 Online:2016-05-20 Published:2016-05-20
  • Contact: Harish C. Pant, Ph.D., panth@ninds.nih.gov.

摘要:

细胞周期蛋白依赖性激酶5(Cdk5),是细胞周期蛋白依赖性激酶的一个家族成员,在神经系统发育和功能中有着关键作用。Cdk5首次提纯作为两种tau蛋白激酶,即TPKI和TPKII酮(TPKII)。美国国立研究院Harish C. Pant研究员所在部门的研究也确定了激酶和磷酸酶在哺乳动物和鱿鱼神经调节神经丝和tau磷酸中的角色,并在一个Cdk5敲除的协作研究中证明了其在神经元发育、功能和存活中的关键作用。他们以前的结果以及Cdk5参与帕金森病的结果表明,Cdk5/ P25已经被确定为帕金森病的首要治疗目标。在最近的研究中,他们对TFP5肽在帕金森病模型中的功效进行了测试。与以往一样,研究观察24小时MPP +培养诱导的Cdk5过度活跃的小脑培养。预处理和TFP5共同培养,是足以显著降低升高的活性的。由于Cdk5/P25抑制剂TFP5在阻断激酶活性中的有效性,文章进一步测试其是否可以影响被复制的脑培养初级多巴胺能神经元。最近得出的数据首次确定腹腔注射肽,TP5进入MPTP诱导的小鼠可以有效加快黑质致密部多巴胺神经元块退化,并且防止纹状体多巴胺及其代谢物损失。另外肽治疗也能改善MPTP诱导的行为缺陷,体内抑制神经炎症,并体外防止MPP +神经毒性。这些结果表明,TFP5/TP5可能是有效的帕金森病的治疗措施。

Abstract:

Cyclin-dependent kinase 5 (Cdk5) is a member of the serine-threonine kinase family of cyclin-dependent kinases. Cdk5 is critical to normal mammalian nervous system development and plays important regulatory roles in multiple cellular functions. Recent evidence indicates that Cdk5 is inappropriately activated in several neurodegenerative conditions, including Parkinson’s disease (PD). 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. During neurotoxicity, p35 is cleaved to form p25. Binding of p25 with Cdk5 leads deregulation of Cdk5 resulting in number of neurodegenerative pathologies. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Here we show that inhibition of p25/Cdk5 hyperactivation through TFP5/TP5, truncated 24-aa peptide derived from the Cdk5 activator p35 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 inhibition of Cdk5/p25-hyperactivation by TFP5/TP5 peptide, which identifies Cdk5/p25 as a potential therapeutic target to reduce neurodegeneration in PD.

Key words: cyclin-dependent kinase 5, Parkinson’s disease, neurodegeneration, therapeutic target, TP5 TFP5/TP5 peptide, MPTP