Mice lacking α-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration
Mice lacking α-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration
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DOI：
10.1016/j.neuro.2004.05.002
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发表时间：
2004-09-01
期刊：
影响因子：
3.4
通讯作者：
Goudreau, JL
中科院分区：
文献类型：
--
作者：
Drolet, RE;Behrouz, B;Goudreau, JL
α-突触核蛋白在帕金森病（PD）发病机制中的功能作用尚未完全了解。α-突触核蛋白缺陷小鼠全身暴露于神经毒素提供了一种直接的方法来评估α-突触核蛋白如何在常见的海洋PD模型中介导细胞死亡。为此，野生型和纯合α-突触核蛋白敲除小鼠接受亚慢性和长期慢性暴露于1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）。在亚慢性模型中，将野生型和α-突触核蛋白敲除小鼠用MPTP（l-25 mg/kg，s.c.）或载体，并在最后一次注射后3天处死。延长的慢性模型由两次注射MPTP（1-20 mg/kg，s.c.）每周一次，持续5周，与丙磺舒（250 mg/kg，i. p.），最后一次注射后3周处死动物。MPTP的亚慢性给药引起纹状体多巴胺（DA）浓度的显著的剂量依赖性降低，而在α-突触核蛋白敲除小鼠中观察到减弱的反应。同样，长期，慢性管理MPTP产生剂量依赖性降低纹状体DA浓度，和相应的损失纹状体囊泡单胺转运蛋白（VMAT-2）蛋白在野生型小鼠。然而，缺乏α-突触核蛋白的小鼠纹状体DA浓度的损失减弱，而没有观察到纹状体VMAT-2蛋白的损失。MPTP的亚慢性和长期慢性给药均引起野生型小鼠中3，4-二羟基苯乙酸（DOPAC）与DA比率的增加，但在缺乏α-突触核蛋白的小鼠中则不然。尽管毒性减弱，但在α-突触核蛋白基因敲除小鼠中观察到乳酸盐浓度升高，长期慢性MPTP给药。本研究的结果提供了证据表明，α-突触核蛋白无效小鼠对MPTP暴露的毒性作用具有减弱的反应，甚至在长时间内，并且对黑质纹状体DA神经元的长期损伤的生化后遗症在具有和不具有α-突触核蛋白表达的小鼠之间是不同的。(C)2004年爱思唯尔公司All rights reserved.
The functional role of a-synuclein in the pathogenesis of Parkinson's disease (PD) is not fully understood. Systemic exposure of alpha-synuclein-deficient mice to neurotoxins provides a direct approach to evaluate how alpha-synuclein may mediate cell death in a common marine model of PD. To this end, wild-type and homozygous alpha-synuclein knock-out mice were treated with sub-chronic and prolonged, chronic exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the sub-chronic model, wild-type and a-synuclein knock-out mice were treated for five consecutive days with MPTP (1-25 mg/kg, s.c.) or vehicle, and sacrificed 3 days,following the last injection. The prolonged, chronic model consisted of two injections of MPTP (1-20 mg/kg, s.c.) per week for 5 weeks, with co-administration of probenecid (250 mg/kg, i.p.), and animals were sacrificed 3 weeks following the last injection. Sub-chronic administration of MPTP caused a dramatic, dose-dependent decrease in striatal dopamine (DA) concentrations, while an attenuated response was observed in a-synuclein knock-out mice. Similarly, prolonged, chronic administration of MPTP produced a dose-dependent decrease in striatal DA concentrations, and a corresponding loss of striatal vesicular monoamine transporter (VMAT-2) protein in wild-type mice. However mice lacking alpha-synuclein had an attenuated loss of striatal DA concentrations, while no loss of striatal VMAT-2 protein was observed. Both sub-chronic and prolonged, chronic administration of MPTP caused an increase in the 3,4-dihydroxyphenylacetic acid (DOPAC) to DA ratio in wild-type mice, but not in mice lacking a-synuclein. Despite attenuated toxicity, elevated lactate concentrations were observed in alpha-synuclein knock-out mice following prolonged, chronic MPTP administration. The results of this study provide evidence that alpha-synuclein null mice have an attenuated response to the toxic effects of MPTP exposure, even over prolonged periods of time and that the biochemical sequela of a protracted insult to nigrostriatal DA neurons are distinct between mice with and without alpha-synuclein expression. (C) 2004 Elsevier Inc. All rights reserved.