Division of Pharmacology and Pharmacotherapy/Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Sci Rep. 2019 Nov 22;9(1):17382. doi: 10.1038/s41598-019-54034-z.
Alpha-synuclein (aSyn) is the main component of Lewy bodies, the histopathological marker in Parkinson's disease (PD), and point mutations and multiplications of the aSyn coding SNCA gene correlate with early onset PD. Therefore, various transgenic mouse models overexpressing native or point-mutated aSyn have been developed. Although these models show highly increased aSyn expression they rarely capture dopaminergic cell loss and show a behavioural phenotype only at old age, whereas SNCA mutations are risk factors for PD with earlier onset. The aim of our study was to re-characterize a transgenic mouse strain carrying both A30P and A53T mutated human aSyn. Our study revealed decreased locomotor activity for homozygous transgenic mice starting from 3 months of age which was different from previous studies with this mouse strain that had behavioural deficits starting only after 7-9 months. Additionally, we found a decreased amphetamine response in locomotor activity and decreased extracellular dopaminergic markers in the striatum and substantia nigra with significantly elevated levels of aSyn oligomers. In conclusion, homozygous transgenic A30P*A53T aSyn mice capture several phenotypes of PD with early onset and could be a useful tool for aSyn studies.
α-突触核蛋白（aSyn）是路易体的主要成分，是帕金森病（PD）的组织病理学标志物，aSyn 编码 SNCA 基因的点突变和扩增与早发性 PD 相关。因此，已经开发了各种过表达天然或点突变 aSyn 的转基因小鼠模型。尽管这些模型表现出高度增加的 aSyn 表达，但它们很少捕获多巴胺能神经元的丢失，并且仅在老年时表现出行为表型，而 SNCA 突变是早发性 PD 的危险因素。我们的研究旨在重新表征携带 A30P 和 A53T 突变的人类 aSyn 的转基因小鼠品系。我们的研究表明，从 3 个月大开始，杂合转基因小鼠的运动活性降低，这与以前使用这种小鼠模型的研究不同，以前的研究表明该模型只有在 7-9 个月后才出现行为缺陷。此外，我们发现运动活性中的安非他命反应降低，纹状体和黑质中的细胞外多巴胺标志物减少，而 aSyn 寡聚物的水平显著升高。总之，杂合转基因 A30P*A53T aSyn 小鼠捕获了早发性 PD 的几种表型，可能是 aSyn 研究的有用工具。
