Parkinson-like syndrome induced by continuous MPTP infusion:: Convergent roles of the ubiquitin-proteasome system and α-synuclein
Parkinson-like syndrome induced by continuous MPTP infusion:: Convergent roles of the ubiquitin-proteasome system and α-synuclein
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DOI：
10.1073/pnas.0409713102
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发表时间：
2005-03-01
影响因子：
11.1
通讯作者：
Südhof, TC
中科院分区：
文献类型：
--
作者：
Fornai, F;Schlüter, OM;Südhof, TC
在动物中，零星注射线粒体毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）选择性损伤多巴胺能神经元，但不能完全重现人类帕金森病的特征。我们现在已经开发了一种小鼠帕金森病模型，该模型基于用渗透微型泵连续给予MPTP，并模仿了人类疾病的许多特征。虽然零星和连续MPTP管理导致严重的纹状体多巴胺耗竭和黑质细胞损失，我们发现，只有连续管理的MPTP产生渐进的行为变化，并引发形成黑质包涵体免疫反应的泛素和α-突触核蛋白。此外，只有持续的MPTP输注引起葡萄糖摄取的长期激活和泛素-蛋白酶体系统的抑制。在缺乏α-突触核蛋白的小鼠中，连续MPTP递送仍然诱导代谢活化，但行为症状和神经元细胞死亡的诱导几乎完全减轻。此外，泛素-蛋白酶体系统的抑制和包涵体的产生减少。这些数据表明，小鼠持续低水平暴露于MPTP导致帕金森样综合征的α-突触核蛋白依赖的方式。
In animals, sporadic injections of the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively damage dopaminergic neurons but do not fully reproduce the features of human Parkinson's disease. We have now developed a mouse Parkinson's disease model that is based on continuous MPTP administration with an osmotic minipump and mimics many features of the human disease. Although both sporadic and continuous MPTP administration led to severe striatal dopamine depletion and nigral cell loss, we find that only continuous administration of MPTP produced progressive behavioral changes and triggered formation of nigral inclusions immunoreactive for ubiquitin and alpha-synuclein. Moreover, only continuous MPTP infusions caused long-lasting activation of glucose uptake and inhibition of the ubiquitin-proteasome system. In mice lacking alpha-synuclein, continuous MPTP delivery still induced metabolic activation, but induction of behavioral symptoms and neuronal cell death were almost completely alleviated. Furthermore, the inhibition of the ubiquitin-proteasome system and the production of inclusion bodies were reduced. These data suggest that continuous low-level exposure of mice to MPTP causes a Parkinson-like syndrome in an alpha-synuclein-dependent manner.