Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons
Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons
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DOI：
10.1016/j.cub.2015.07.050
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发表时间：
2015-09-21
期刊：
影响因子：
9.2
通讯作者：
Trudeau, Louis-Eric
中科院分区：
文献类型：
--
作者：
Pacelli, Consiglia;Giguere, Nicolas;Trudeau, Louis-Eric
虽然帕金森氏病神经元丢失的机制还不清楚，但线粒体功能受损和病理性蛋白质聚集被怀疑起主要作用。为什么DA（多巴胺）神经元和一小部分脑核特别容易受到这种普遍存在的细胞功能障碍的影响，这是目前帕金森病研究中尚未回答的关键问题之一。一个有趣的假设是，他们的高度脆弱性是他们提高生物能量需求的结果。在这里，我们第一次表明，脆弱的黑质DA神经元不同于不太脆弱的DA神经元，如腹侧被盖区（腹侧被盖区）的线粒体OXPHOS（氧化磷酸化）的基础率较高，储备容量较小，轴突线粒体的密度较高，基础氧化应激水平升高，以及相当复杂的轴突分支。此外，我们证明，通过使用脑信号蛋白7A作用于轴突引导途径来减少轴突树枝化，同时降低了线粒体OXPHOS的基础速率以及黑质DA神经元对神经毒剂MPP+（1-甲基-4-苯基吡啶）和鱼藤酮的脆弱性。用伊拉地平阻断L型钙通道对MPP+有保护作用，但对鱼藤酮无保护作用。我们的数据提供了迄今为止最直接的证据，支持帕金森病中黑质DA神经元的脆弱性增加直接归因于其特定的生物能量和形态学特征的假设。
Although the mechanisms underlying the loss of neurons in Parkinson's disease are not well understood, impaired mitochondrial function and pathological protein aggregation are suspected as playing a major role. Why DA (dopamine) neurons and a select small subset of brain nuclei are particularly vulnerable to such ubiquitous cellular dysfunctions is presently one of the key unanswered questions in Parkinson's disease research. One intriguing hypothesis is that their heightened vulnerability is a consequence of their elevated bioenergetic requirements. Here, we show for the first time that vulnerable nigral DA neurons differ from less vulnerable DA neurons such as those of the VTA (ventral tegmental area) by having a higher basal rate of mitochondrial OXPHOS (oxidative phosphorylation), a smaller reserve capacity, a higher density of axonal mitochondria, an elevated level of basal oxidative stress, and a considerably more complex axonal arborization. Furthermore, we demonstrate that reducing axonal arborization by acting on axon guidance pathways with Semaphorin 7A reduces in parallel the basal rate of mitochondrial OXPHOS and the vulnerability of nigral DA neurons to the neurotoxic agents MPP+ (1-methyl-4-phenylpyridinium) and rotenone. Blocking L-type calcium channels with isradipine was protective against MPP+ but not rotenone. Our data provide the most direct demonstration to date in favor of the hypothesis that the heightened vulnerability of nigral DA neurons in Parkinson's disease is directly due to their particular bioenergetic and morphological characteristics.