Division of Pharmacology and Toxicology, Faculty of Pharmacy, P.O. Box 56, FIN-00014 University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland.
Neuroscience. 2013 Feb 12;231:157-68. doi: 10.1016/j.neuroscience.2012.11.045. Epub 2012 Dec 4.
Three point mutations in the SNCA gene encoding α-synuclein (aSyn) have been associated with autosomal dominant forms of Parkinson's disease. To better understand the role of the A30P mutant aSyn, we compared two transgenic mouse strains: a knock-in mouse with an introduced A30P point mutation in the wild-type (WT) gene (Snca(tm(A30P))) and a transgenic (Tg) mouse overexpressing the human A30P aSyn gene under the prion promoter [tg(Prnp-SNCA A30P)]. The brain aSyn load, motor performance, brain dopamine (DA) and sensitivity to 6-hydroxydopamine (6-OHDA) were studied in these mice. aSyn was evidently accumulating with age in all mice, particularly in tg(Prnp-SNCA A30P) Tg mice. There were no robust changes in basal locomotor activities of the mice of either line at 6 months, but after 1 year, tg(Prnp-SNCA A30P) Tg mice developed severe problems with vertical movements. However, the younger Tg mice had a reduced locomotor response to 1mg/kg of d-amphetamine. Snca(tm(A30P)) mice with the targeted mutation (Tm) were slightly hyperactive at all ages. Less 6-OHDA was required in tg(Prnp-SNCA A30P) Tg (1 μg) than in WT (3μg) mice for an ipsilateral rotational bias by d-amphetamine. That was not seen with the Snca(tm(A30P)) strain. A small dose of 6-OHDA (0.33 μg) led to contralateral rotations and elevated striatal DA in Tg/Tm mice of both lines but otherwise 6-OHDA-induced striatal DA depletion was similar in all mice, indicating no A30P-aSyn-related toxin sensitivity. 3,4-Dihydroxyphenylacetic acid/DA-ratio was elevated in tg(Prnp-SNCA A30P) mice, suggesting an enhanced DA turnover. This ratio and homovanillic acid/DA-ratio were declined in Snca(tm(A30P)) mice. Our results demonstrate that the two differently constructed A30P-aSyn mouse strains have distinct behavioral and biochemical characteristics, some of which are opposite. Since the two lines with the same background were not identically produced, the deviations found may be partially caused by factors other than aSyn-related genetic differences.
三个点突变在 SNCA 基因编码的 α-突触核蛋白（aSyn）已与常染色体显性形式的帕金森病有关。为了更好地了解 A30P 突变 aSyn 的作用，我们比较了两种转基因小鼠品系：一种是在野生型（WT）基因中引入 A30P 点突变的敲入小鼠（Snca(tm(A30P)))，另一种是在朊病毒启动子下过表达人类 A30P aSyn 基因的转基因（Tg）小鼠[tg(Prnp-SNCA A30P)]。在这些小鼠中研究了脑内 aSyn 负荷、运动表现、脑多巴胺（DA）和对 6-羟多巴胺（6-OHDA）的敏感性。在所有小鼠中，aSyn 随着年龄的增长明显积累，特别是在 tg(Prnp-SNCA A30P)Tg 小鼠中。在 6 个月时，这两种品系的小鼠的基础运动活动没有明显变化，但在 1 年后，Tg(Prnp-SNCA A30P)Tg 小鼠出现严重的垂直运动问题。然而，年轻的 Tg 小鼠对 1mg/kg 的 d-苯丙胺的运动反应减少。具有靶向突变（Tm）的 Snca(tm(A30P))小鼠在所有年龄段都略有过度活跃。与 WT（3μg）小鼠相比，用 d-苯丙胺诱导的 ipsilateral 旋转偏倚，需要更少的 tg(Prnp-SNCA A30P)Tg（1μg）小鼠中的 6-OHDA。在 Snca(tm(A30P)) 品系中未观察到这种情况。两种线中的 Tg/Tm 小鼠中，小剂量的 6-OHDA（0.33μg）导致对侧旋转和纹状体 DA 升高，但否则，所有小鼠中的 6-OHDA 诱导的纹状体 DA 耗竭相似，表明没有与 A30P-aSyn 相关的毒素敏感性。Tg(Prnp-SNCA A30P)小鼠中的 3,4-二羟苯乙酸/DA 比值升高，提示 DA 周转率增强。Snca(tm(A30P))小鼠中的该比值和高香草酸/DA 比值下降。我们的结果表明，两种不同构建的 A30P-aSyn 小鼠品系具有不同的行为和生化特征，其中一些特征是相反的。由于具有相同背景的两条线并非完全相同产生，因此发现的偏差可能部分是由 aSyn 相关遗传差异以外的因素引起的。
