Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
Division of Neurosciences, NIA-NIH, Bethesda, USA.
Neurobiol Aging. 2021 May;101:207-220. doi: 10.1016/j.neurobiolaging.2021.01.010. Epub 2021 Jan 28.
The pathogenesis of Parkinson's disease involves fibrillization and deposition of alpha-synuclein (α-syn) into Lewy bodies. Accumulating evidence suggests that α-syn oligomers are particularly neurotoxic. Transgenic (tg) mice overexpressing wild-type human α-syn under the Thy-1 promoter (L61) reproduce many Parkinson's disease features, but the pathogenetic relevance of α-syn oligomers in this mouse model has not been studied in detail. Here, we report an age progressive increase of α-syn oligomers in the brain of L61 tg mice. Interestingly, more profound motor symptoms were observed in animals with higher levels of membrane-bound oligomers. As this tg model is X-linked, we also performed subset analyses, indicating that both sexes display a similar age-related increase in α-syn oligomers. However, compared with females, males featured increased brain levels of oligomers from an earlier age, in addition to a more severe behavioral phenotype with hyperactivity and thigmotaxis in the open field test. Taken together, our data indicate that α-syn oligomers are central to the development of brain pathology and behavioral deficits in the L61 tg α-syn mouse model.
帕金森病的发病机制涉及α-突触核蛋白（α-syn）的纤维形成和沉积到路易小体中。越来越多的证据表明，α-syn 寡聚物特别具有神经毒性。在 Thy-1 启动子（L61）下过度表达野生型人α-syn 的转基因（tg）小鼠再现了许多帕金森病的特征，但这种小鼠模型中α-syn 寡聚物的发病相关性尚未详细研究。在这里，我们报告了 L61 tg 小鼠脑中α-syn 寡聚物随年龄的逐渐增加。有趣的是，在具有更高水平膜结合寡聚物的动物中观察到更严重的运动症状。由于该 tg 模型是 X 连锁的，我们还进行了亚组分析，表明两性均表现出与年龄相关的α-syn 寡聚物的相似增加。然而，与女性相比，男性从更早的年龄开始就具有更高的大脑寡聚物水平，此外在旷场测试中还表现出过度活跃和触壁行为的更严重行为表型。总之，我们的数据表明，α-syn 寡聚物是 L61 tg α-syn 小鼠模型中脑病理学和行为缺陷发展的核心。
