MitoPark mice mirror the slow progression of key symptoms and L-DOPA response in Parkinson's disease.
MitoPark mice mirror the slow progression of key symptoms and L-DOPA response in Parkinson's disease.
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DOI：
10.1111/j.1601-183x.2009.00542.x
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发表时间：
2010-03-01
期刊：
影响因子：
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通讯作者：
Olson L
中科院分区：
文献类型：
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作者：
Galter D;Pernold K;Yoshitake T;Lindqvist E;Hoffer B;Kehr J;Larsson NG;Olson L
MitoPark 小鼠的中脑多巴胺 (DA) 神经元中的线粒体转录因子 Tfam 被选择性去除，该小鼠是帕金森病 (PD) 的遗传模型，可复制关键症状的缓慢进行性发展。为了进一步验证该模型，我们对这些动物进行了行为和生化分析。我们发现垂直运动比水平运动下降得更早、更快，这可能模拟了帕金森病中早期发生的轴向、姿势不稳定。 L-DOPA 根据年龄诱导不同的运动反应：在年轻的 MitoPark 小鼠中，L-DOPA 诱导的运动激活很小；而在年轻的 MitoPark 小鼠中，L-DOPA 诱导的运动激活很小；中年 MitoPark 小鼠对 L-DOPA 的反应呈剂量依赖性，而老年 MitoPark 小鼠对高剂量 L-DOPA 表现出双峰运动反应，其中包括运动活动非常低的间歇期，类似于 PD 中的“开关”现象。为了将行为与生化数据联系起来，我们分析了受 DA 系统高度支配的三个不同大脑区域的单胺水平：纹状体、前皮质和嗅球。纹状体中的 DA 水平比皮质中下降得更早、更快；仅在分析的最后一个时间点，发现嗅球中的 DA 水平显着低于对照水平。有趣的是，随着时间的推移，高香草酸 (HVA) 和 DA 之间的比例在不同地区之间存在差异。在纹状体和嗅球中，该比率急剧增加，表明 DA 周转率增加。相反，皮质中的比率随着时间的推移而下降，揭示了黑质和腹侧被盖区的 DA 细胞之间的重要差异。
The MitoPark mouse, in which the mitochondrial transcription factor Tfam is selectively removed in midbrain dopamine (DA) neurons, is a genetic model for Parkinson’s disease (PD) that replicates the slow and progressive development of key symptoms. To further validate this model, we have extended both behavioral and biochemical analyses in these animals. We found that vertical movements decline earlier and faster than horizontal movements, possibly modeling the early occurrence of axial, postural instability in PD. L-DOPA induces different locomotor responses depending on the age: in young MitoPark mice the L-DOPA-induced motor activation is small; middle-aged MitoPark mice respond in a dose-dependent manner to L-DOPA, whereas aged MitoPark mice display a double-peaked locomotor response to a high dose of L-DOPA that includes an intermittent period of very low motor activity, similar to the ‘on–off’ phenomenon in PD. To correlate behavior with biochemical data, we analyzed monoamine levels in three different brain areas that are highly innervated by the DA system: striatum, anterior cortex and olfactory bulb. DA levels declined earlier and faster in striatum than in cortex; only at the latest time-point analyzed, DA levels were found to be significantly lower than control levels in the olfactory bulb. Interestingly, the ratio between homovanillic acid (HVA) and DA differed between regions over time. In striatum and olfactory bulb, the ratio increased steeply indicating increased DA turnover. In contrast, the ratio decreased over time in cortex, revealing important differences between DA cells in substantia nigra and the ventral tegmental area.