Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, Lausanne, CH-1015, Switzerland.
Laboratory of Behavioral Genetics, Brain Mind Institute, EPFL, Lausanne, CH-1015, Switzerland.
eNeuro. 2020 Aug 17;7(4). doi: 10.1523/ENEURO.0110-20.2020. Print 2020 Jul/Aug.
Increasing evidence suggests that cross talk between α-synuclein pathology formation and mitochondrial dysfunction plays a central role in the pathogenesis of Parkinson's disease (PD) and related synucleinopathies. While mitochondrial dysfunction is a well-studied phenomenon in the substantia nigra, which is selectively vulnerable in PD and some models thereof, less information is available in other brain regions that are also affected by synuclein pathology. Therefore, we sought to test the hypothesis that early α-synuclein pathology causes mitochondrial dysfunction and that this effect might be exacerbated in conditions of increased vulnerability in affected brain regions, such as the amygdala. We combined a model of intracerebral α-synuclein pathology seeding with chronic glucocorticoid treatment, which models non-motor symptoms of PD and affects amygdala physiology. We measured mitochondrial respiration, reactive oxygen species (ROS) generation and protein abundance as well as α-synuclein pathology in male mice. Chronic corticosterone administration induced mitochondrial hyperactivity in the amygdala. Although injection of α-synuclein preformed fibrils (PFFs) into the striatum resulted in pronounced α-synuclein pathology in both striatum and amygdala, mitochondrial respiration in these brain regions was not compromised, regardless of corticosterone treatment. Our results suggest that early stage α-synuclein pathology does not influence mitochondrial respiration in the striatum and amygdala, even in corticosterone-induced respirational hyperactivity. We discuss our findings in light of relevant literature, warn of a potential publication bias and encourage scientists to report their negative results within the framework of this model.
越来越多的证据表明，α-突触核蛋白病理形成与线粒体功能障碍之间的串扰在帕金森病（PD）和相关突触核蛋白病的发病机制中起着核心作用。虽然线粒体功能障碍是黑质中研究得很好的现象，黑质在 PD 及其一些模型中是选择性易损的，但在其他也受到突触核蛋白病理影响的脑区，信息较少。因此，我们试图验证这样一个假设，即早期的α-突触核蛋白病理导致线粒体功能障碍，并且这种效应在受影响的脑区（如杏仁核）的易损性增加的情况下可能会加剧。我们结合了脑内α-突触核蛋白病理播散模型和慢性糖皮质激素治疗，该模型模拟 PD 的非运动症状并影响杏仁核生理学。我们测量了雄性小鼠的线粒体呼吸、活性氧（ROS）生成和蛋白质丰度以及α-突触核蛋白病理。慢性皮质酮给药诱导杏仁核中线粒体过度活跃。尽管将α-突触核蛋白原纤维形成物（PFFs）注射到纹状体中会导致纹状体和杏仁核中明显的α-突触核蛋白病理，但这些脑区的线粒体呼吸并没有受到影响，无论是否存在皮质酮治疗。我们的结果表明，即使在皮质酮诱导的呼吸过度活跃的情况下，早期的α-突触核蛋白病理也不会影响纹状体和杏仁核中的线粒体呼吸。我们根据相关文献讨论了我们的发现，警告了潜在的发表偏倚，并鼓励科学家在该模型的框架内报告他们的阴性结果。
