Cdk5/p25 specific inhibitory peptide TFP5 rescues the loss of dopaminergic neurons in a sub-acute MPTP induced PD mouse model
Cdk5/p25 specific inhibitory peptide TFP5 rescues the loss of dopaminergic neurons in a sub-acute MPTP induced PD mouse model
复制标题
Cdk5/p25特异性抑制肽TFP5可挽救亚急性MPTP诱导的PD小鼠模型中多巴胺能神经元的丧失
DOI：
10.1016/j.neulet.2016.08.023
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发表时间：
2016-10
影响因子：
2.5
通讯作者：
Yafang Hu
中科院分区：
文献类型：
--
作者：
Yong He;Jianou Huang;Suyue Pan;Yafang Hu
帕金森病（Parkinson's disease，PD）的病理特征是黑质多巴胺能（dopaminergic，DA）神经元的进行性丢失和路易体的形成。在1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的PD小鼠模型中，钙蛋白酶-细胞周期蛋白依赖性激酶5（Cdk 5）-肌细胞增强因子2（MEF 2）信号传导已被证明可以控制多巴胺能神经元死亡。在MPTP损伤下，p35被钙蛋白酶切割成p25，p25与Cdk 5结合并表现出Cdk 5/p25的高活性。Cdk 5/p25使存活因子MEF 2失活，MEF 2对DA神经元死亡至关重要。在这项研究中，通过腹膜内（i. p.）注射MPTP连续5天。结果表明，亚急性MPTP小鼠肺组织中p35、p25表达水平及p25/p35比值均升高。腹腔注射后，TFP 5广泛到达皮质神经元、海马和SNpc区域。与盐水处理组相比，用45 mg/kg/天TFP 5以及10 mg/kg/天Cdk 5抑制剂roscovitine预处理三天分别显著挽救了高达9.8%或9.7%的DA神经元损失。TFP 5和roscovitine处理降低了MEF 2的失活形式和切割的caspase 3的水平，从而保护DA神经元的凋亡免受MPTP损伤。我们的研究结果表明，TFP 5可能是PD的潜在治疗候选者。
Parkinson's disease (PD) is pathologically characterized by progressively loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the formation of Lewy bodies. In 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) induced PD mice models, the calpain- cyclin-dependent kinase 5 (Cdk5)-myocyte enhancer factor 2 (MEF2) signaling has been proven in governing dopaminergic neuronal death. Under MPTP insult, p35 is cleaved by calpain into p25, which binds to Cdk5 and exhibits hyperactivity of Cdk5/p25. Cdk5/p25 inactivates MEF2, a survivor factor, which is critical for DA neuronal death. In this study, neuroprotective effect of the Cdk5/p25 specific peptide, TFP5, was evaluated in sub-acute MPTP induced PD mouse model by intraperitoneal (i.p.) injection of MPTP for five consecutive days. The results indicated that the levels of p35 and p25, and p25/p35 ratio increased in the sub-acute MPTP mice. TFP5 broadly reached cortex neuron, hippocampus and SNpc areas after i.p. injections. Pretreatment with 45 mg/kg/day TFP5, as well as 10 mg kg/day Cdk5 inhibitor roscovitine, for three days significantly rescued DA neuronal loss up to 9.8% or 9.7% respectively compared to the saline treated group. Treatment of TFP5 and roscovitine reduced the levels of inactive form of MEF2 and cleaved caspase 3, thus protected apoptosis of DA neurons against MPTP insult. Our results propose that TFP5 might be a potential therapeutic candidate for PD.
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影响因子：
14.8
作者：
Jackson-Lewis, Vernice;Przedborski, Serge
通讯作者：
Przedborski, Serge
DOI：
10.1073/pnas.1212914109
发表时间：
2012-12-04
影响因子：
11.1
作者：
Zhang, Lingyan;Liu, Wen;Lew, John
通讯作者：
Lew, John
影响因子：
16.2
作者：
Qu, Dianbo;Rashidian, Juliet;Park, David S.
通讯作者：
Park, David S.
影响因子：
4.2
作者：
T. Town;Joseph Zolton;Reed Shaffner;Billy Schnell;Robert M. Crescentini;Yajuan Wu;J. Zeng;A. Delledonne;Demian F. Obregon;Jun Tan;M. Mullan
通讯作者：
T. Town;Joseph Zolton;Reed Shaffner;Billy Schnell;Robert M. Crescentini;Yajuan Wu;J. Zeng;A. Delledonne;Demian F. Obregon;Jun Tan;M. Mullan
影响因子：
11.4
作者：
Zheng, YL;Kesavapany, S;Pant, HC
通讯作者：
Pant, HC