How compensation breaks down in Parkinson's disease: Insights from modeling of denervated striatum
How compensation breaks down in Parkinson's disease: Insights from modeling of denervated striatum
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DOI：
10.1002/mds.26579
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发表时间：
2016-03-01
影响因子：
8.6
通讯作者：
Dreyer, Jakob Kisbye
中科院分区：
文献类型：
--
作者：
Navntoft, Charlotte Amalie;Dreyer, Jakob Kisbye
帕金森病（PD）的运动迟缓和其他运动体征与支配纹状体的黑质多巴胺（DA）神经元的进行性丧失有关。然而，特发性PD的出现可能是由一个长期的亚临床阶段，这可能是由各种突触前和突触后代偿机制掩盖。通常认为，PD的体征仅在黑质纹状体变性进行到假定的代偿机制无法适应纹状体DA水平耗竭的程度时才表现出来，这是不言而喻的。然而，补偿机制的确切性质及其最终失败的原因一直难以捉摸。在最近的一项计算研究中，我们模拟了进行性去神经支配的影响，包括间质DA的动态变化，以及在进行性黑质纹状体变性过程中对DA信号的突触后反应性的适应性或补偿性变化。特别是，我们发现DA信号传导的失败可以在不同的疾病阶段通过不同的机制发生。我们回顾了这些结果，并讨论了它们与临床和转化研究的相关性，我们从我们的模型中得出了一些预测，这些预测可能会在临床前实验中进行测试。(c)2016作者出版社：Wiley Periodicals，Inc.国际帕金森和运动障碍协会（International Parkinson and Movement Disorder Society）
The bradykinesia and other motor signs of Parkinson's disease (PD) are linked to progressive loss of substantia nigra dopamine (DA) neurons innervating the striatum. However, the emergence of idiopathic PD is likely preceded by a prolonged subclinical phase, which may be masked by a variety of pre- and postsynaptic compensatory mechanisms. It is often considered self-evident that the signs of PD manifest only when nigrostriatal degeneration has proceeded to such an extent that putative compensatory mechanisms fail to accommodate the depletion of striatal DA levels. However, the precise nature of the compensatory mechanisms, and the reason for their ultimate failure, has been elusive. In a recent computational study we modeled the effects of progressive denervation, including changes in the dynamics of interstitial DA and also adaptive or compensatory changes in postsynaptic responsiveness to DA signaling in the course of progressive nigrostriatal degeneration. In particular, we found that failure of DA signaling can occur by different mechanisms at different disease stages. We review these results and discuss their relevance for clinical and translational research, and we draw a number of predictions from our model that might be tested in preclinical experiments. (c) 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.