CURE/Digestive Disease Research Center, Med/Digestive, David Geffen Medical School, UCLA, Los Angeles, CA, USA.
Drug Discovery Lab, Department of Neurology, UCLA, Los Angeles, CA, USA.
J Alzheimers Dis. 2021;79(2):875-893. doi: 10.3233/JAD-200983.
Alpha-synuclein (α-syn) is involved in pathology of Parkinson's disease, and 90% of α-syn in Lewy bodies is phosphorylated at serine 129 (pS129 α-syn).
To assess behavior impairments and brain levels of α-syn and pS129 α-syn in mice overexpressing human α-syn under Thy1 promoter (Thy1-α-syn) and wild type (wt) littermates.
Motor and non-motor behaviors were monitored, brain human α-syn levels measured by ELISA, and α-syn and pS129 α-syn mapped by immunohistochemistry.
Male and female wt littermates did not show differences in the behavioral tests. Male Thy1-α-syn mice displayed more severe impairments than female counterparts in cotton nesting, pole tests, adhesive removal, finding buried food, and marble burying. Concentrations of human α-syn in the olfactory regions, cortex, nigrostriatal system, and dorsal medulla were significantly increased in Thy1-α-syn mice, higher in males than females. Immunoreactivity of α-syn was not simply increased in Thy1-α-syn mice but had altered localization in somas and fibers in a few brain areas. Abundant pS129 α-syn existed in many brain areas of Thy1-α-syn mice, while there was none or only a small amount in a few brain regions of wt mice. The substantia nigra, olfactory regions, amygdala, lateral parabrachial nucleus, and dorsal vagal complex displayed different distribution patterns between wt and transgenic mice, but not between sexes.
The severer abnormal behaviors in male than female Thy1-α-syn mice may be related to higher brain levels of human α-syn, in the absence of sex differences in the altered brain immunoreactivity patterns of α-syn and pS129 α-syn.
α-突触核蛋白（α-syn）参与帕金森病的病理学，路易小体中 90%的α-syn 是丝氨酸 129 磷酸化的（pS129α-syn）。
评估过表达人源α-syn 于 Thy1 启动子（Thy1-α-syn）的小鼠和野生型（wt）同窝仔鼠的行为障碍和脑内α-syn 及 pS129α-syn 水平。
监测运动和非运动行为，通过 ELISA 测定脑内人源α-syn 水平，并用免疫组化定位α-syn 和 pS129α-syn。
雄性和雌性 wt 同窝仔鼠在行为测试中没有差异。雄性 Thy1-α-syn 小鼠在棉絮嵌套、棒测试、粘胶去除、寻找埋藏的食物和大理石埋藏测试中比雌性对照表现出更严重的障碍。Thy1-α-syn 小鼠嗅区、皮质、黑质纹状体系统和背侧延髓中的人源α-syn 浓度显著增加，雄性高于雌性。Thy1-α-syn 小鼠的α-syn 免疫反应性不仅增加，而且在少数脑区的体和纤维中有改变的定位。大量的 pS129α-syn 存在于 Thy1-α-syn 小鼠的许多脑区，而 wt 小鼠的少数脑区中则不存在或只有少量。黑质、嗅区、杏仁核、外侧臂旁核和背侧迷走复合体在 wt 和转基因小鼠之间显示出不同的分布模式，但在性别之间没有差异。
雄性 Thy1-α-syn 小鼠比雌性更严重的异常行为可能与更高的脑内人源α-syn 水平有关，而在α-syn 和 pS129α-syn 的脑免疫反应性改变模式中没有性别差异。
