Crocker Stephen J, Smith Patrice D, Jackson-Lewis Vernice, Lamba Wiplore R, Hayley Shawn P, Grimm Erich, Callaghan Steve M, Slack Ruth S, Melloni Edon, Przedborski Serge, Robertson George S, Anisman Hymie, Merali Zul, Park David S
Neuroscience Research Group, Ottawa Health Research Institute, Canada.
J Neurosci. 2003 May 15;23(10):4081-91. doi: 10.1523/JNEUROSCI.23-10-04081.2003.
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.
帕金森病（PD）中脑多巴胺神经元变性的分子机制尚不清楚。在此，我们提供证据支持钙依赖性蛋白酶钙蛋白酶参与PD小鼠模型中多巴胺神经元丧失的作用。我们表明，给予N-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）可在体内引起黑质多巴胺神经元中钙蛋白酶介导的蛋白水解增加。使用钙蛋白酶抑制剂（MDL-28170）或腺病毒介导的内源性钙蛋白酶抑制剂蛋白钙蛋白酶抑制蛋白的过表达来抑制钙蛋白酶的蛋白水解，可显著减轻MPTP诱导的黑质多巴胺神经元丧失。与这种神经保护作用相一致，MPTP诱导的运动缺陷被消除，并且在钙蛋白酶抑制剂处理的小鼠中纹状体突触后活动的标志物恢复正常。然而，MPTP处理的、钙蛋白酶抑制的小鼠的行为改善与纹状体多巴胺水平的恢复无关。这些结果表明，对PD中黑质神经元变性的保护可能足以促进正常的运动活动，而无需纹状体重新支配。对人类PD病例死后中脑组织的免疫组织化学分析也显示出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并不明显。综上所述，我们的研究结果提供了PD的MPTP模型中钙蛋白酶蛋白水解活性与人类PD中神经元丧失病因之间潜在的新关联。
