Adeosun Samuel O, Hou Xu, Zheng Baoying, Melrose Heather L, Mosley Thomas, Wang Jun Ming
Department of Pathology, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, United States.
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd S, Jacksonville, FL 32224, United States.
Neurobiol Learn Mem. 2017 Jul;142(Pt B):182-189. doi: 10.1016/j.nlm.2017.05.001. Epub 2017 May 6.
LRRK2 G2019S mutation is associated with increased kinase activity and is the most common mutation associated with late-onset PD. However, the transgenic mouse model has not recapitulated cardinal PD-related motor phenotypes. Non-motor symptoms of PD including cognitive impairments are very common and may appear earlier than the motor symptoms. The objective of this study was to determine whether human LRRK2 with G2019S mutation causes hippocampus-dependent cognitive deficits in mice.
Male (LRRK2-G2019S) LRRK2-Tg mice showed impairments in the early portion of the Two-day radial arm water maze acquisition trial as well as in the reversal learning on the third day. However, their performance was similar to Non-Tg controls in the probe trial. LRRK2-Tg mice also displayed impairments in the novel arm discrimination test but not in the spontaneous alternation test in Y-maze. Interestingly, there was no statistically significant locomotor impairment during any of these cognitive test, nor in the locomotor tests including open field, accelerating rotarod and pole tests. Expression of the postsynaptic protein PSD-95 but not the presynaptic protein synaptophysin was lower in hippocampal homogenates of LRRK2-Tg mice.
Consistent with previous reports in human LRRK2 G2019S carriers, the current data suggests that cognitive dysfunctions are present in LRRK2-Tg mice even in the absence of locomotor impairment. LRRK2 G2019S mutation represses the postsynaptic protein PSD-95 but not the presynaptic protein synaptophysin. This study also suggests that mild cognitive impairment may appear earlier than motor dysfunctions in LRRK2-G2019S mutation carriers.
LRRK2基因G2019S突变与激酶活性增加相关，是与晚发型帕金森病相关的最常见突变。然而，转基因小鼠模型并未重现帕金森病相关的主要运动表型。帕金森病的非运动症状包括认知障碍非常常见，且可能比运动症状出现得更早。本研究的目的是确定携带G2019S突变的人LRRK2是否会导致小鼠出现海马体依赖性认知缺陷。
雄性（LRRK2-G2019S）LRRK2转基因小鼠在为期两天的放射状臂水迷宫获取试验的早期以及第三天的逆向学习中表现受损。然而，在探针试验中它们的表现与非转基因对照组相似。LRRK2转基因小鼠在新臂辨别试验中也表现受损，但在Y迷宫的自发交替试验中未受损。有趣的是，在任何这些认知测试过程中，以及在包括旷场试验、加速转棒试验和杆试验在内的运动测试中，均未出现统计学上显著的运动障碍。LRRK2转基因小鼠海马匀浆中突触后蛋白PSD-95的表达降低，而突触前蛋白突触素的表达未降低。
与先前关于人类LRRK2 G2019S携带者的报道一致，当前数据表明，即使在没有运动障碍的情况下，LRRK2转基因小鼠也存在认知功能障碍。LRRK2 G2019S突变会抑制突触后蛋白PSD-95，但不抑制突触前蛋白突触素。本研究还表明，在LRRK2-G2019S突变携带者中，轻度认知障碍可能比运动功能障碍出现得更早。
