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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Inhibition of calpains prevents neuronal and behavioral deficits in an MPTP mouse model of Parkinson's disease.
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Inhibition of calpains prevents neuronal and behavioral deficits in an MPTP mouse model of Parkinson's disease.

机译：抑制钙蛋白酶可预防帕金森氏病MPTP小鼠模型中的神经元和行为缺陷。

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The molecular mechanisms mediating degeneration of midbrain dopamine neurons in Parkinson's disease (PD) are poorly understood. Here, we provide evidence to support a role for the involvement of the calcium-dependent proteases, calpains, in the loss of dopamine neurons in a mouse model of PD. We show that administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) evokes an increase in calpain-mediated proteolysis in nigral dopamine neurons in vivo. Inhibition of calpain proteolysis using either a calpain inhibitor (MDL-28170) or adenovirus-mediated overexpression of the endogenous calpain inhibitor protein, calpastatin, significantly attenuated MPTP-induced loss of nigral dopamine neurons. Commensurate with this neuroprotection, MPTP-induced locomotor deficits were abolished, and markers of striatal postsynaptic activity were normalized in calpain inhibitor-treated mice. However, behavioral improvements in MPTP-treated, calpain inhibited mice did not correlate with restored levels of striatal dopamine. These results suggest that protection against nigral neuron degeneration in PD may be sufficient to facilitate normalized locomotor activity without necessitating striatal reinnervation. Immunohistochemical analyses of postmortem midbrain tissues from human PD cases also displayed evidence of increased calpain-related proteolytic activity that was not evident in age-matched control subjects. Taken together, our findings provide a potentially novel correlation between calpain proteolytic activity in an MPTP model of PD and the etiology of neuronal loss in PD in humans.
机译：在帕金森氏病（PD）中介导中脑多巴胺神经元变性的分子机制了解甚少。在这里，我们提供证据支持钙依赖性蛋白酶钙蛋白酶在PD小鼠模型中多巴胺神经元丢失中的作用。我们显示，N-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）的使用引起体内钙蛋白酶介导的蛋白水解在黑质多巴胺神经元中的增加。使用钙蛋白酶抑制剂（MDL-28170）或腺病毒介导的内源钙蛋白酶抑制剂蛋白calpastatin的过表达抑制钙蛋白酶蛋白水解，可显着减弱MPTP诱导的黑质多巴胺神经元损失。与此神经保护相称，在钙蛋白酶抑制剂治疗的小鼠中，MPTP引起的运动功能障碍被消除，纹状体突触后活性的标记物被标准化。但是，MPTP处理，钙蛋白酶抑制的小鼠的行为改善与纹状体多巴胺的恢复水平无关。这些结果表明，针对PD中的黑色神经元变性的保护可能足以促进正常的运动活动，而无需纹状体神经支配。人类PD病例的死后中脑组织的免疫组织化学分析也显示了钙蛋白酶相关蛋白水解活性增加的证据，这在年龄匹配的对照受试者中不明显。综上所述，我们的发现为PD的MPTP模型中的钙蛋白酶蛋白水解活性与人类PD的神经元丢失的病因学之间提供了潜在的新颖关联。

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