Human LRRK2 G2019S mutation represses post-synaptic protein PSD95 and causes cognitive impairment in transgenic mice.
Human LRRK2 G2019S mutation represses post-synaptic protein PSD95 and causes cognitive impairment in transgenic mice.
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人LRRK2 G2019S突变抑制后突触蛋白PSD95，并导致转基因小鼠的认知障碍。
DOI：
10.1016/j.nlm.2017.05.001
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发表时间：
2017-07
影响因子：
2.7
通讯作者：
Wang JM
中科院分区：
文献类型：
--
作者：
Adeosun SO;Hou X;Zheng B;Melrose HL;Mosley T;Wang JM
LRRK 2 G2019 S突变与激酶活性增加相关，是与晚发型PD相关的最常见突变。然而，转基因小鼠模型并没有概括主要的PD相关的运动表型。PD的非运动症状（包括认知障碍）非常常见，可能比运动症状更早出现。本研究的目的是确定具有G2019 S突变的人LRRK 2是否导致小鼠的海马依赖性认知缺陷。雄性（LRRK 2-G2019 S）LRRK 2-Tg小鼠在两天径向臂水迷宫获取试验的早期部分以及第三天的逆转学习中显示出损伤。然而，在探针试验中，它们的性能与非Tg对照相似。LRRK 2-Tg小鼠在新的手臂辨别测试中也显示出损伤，但在Y-迷宫中的自发交替测试中没有。有趣的是，在任何这些认知测试中，也没有统计学上显著的运动障碍，包括旷场，加速旋转杆和杆测试的运动测试。LRRK 2-Tg小鼠海马匀浆中突触后蛋白PSD-95的表达较低，但突触前蛋白突触素的表达不高。与先前在人LRRK 2 G2019 S携带者中的报道一致，当前数据表明，即使在没有运动障碍的情况下，LRRK 2-Tg小鼠中也存在认知功能障碍。LRRK 2 G2019 S突变抑制突触后蛋白PSD-95，但不抑制突触前蛋白突触素。这项研究还表明，在LRRK 2-G2019 S突变携带者中，轻度认知障碍可能比运动功能障碍更早出现。
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.
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影响因子：
6.1
作者：
Melrose HL;Dächsel JC;Behrouz B;Lincoln SJ;Yue M;Hinkle KM;Kent CB;Korvatska E;Taylor JP;Witten L;Liang YQ;Beevers JE;Boules M;Dugger BN;Serna VA;Gaukhman A;Yu X;Castanedes-Casey M;Braithwaite AT;Ogholikhan S;Yu N;Bass D;Tyndall G;Schellenberg GD;Dickson DW;Janus C;Farrer MJ
通讯作者：
Farrer MJ
影响因子：
25
作者：
Li, Yanping;Liu, Wencheng;Oo, Tinmarla F.;Wang, Lei;Tang, Yi;Jackson-Lewis, Vernice;Zhou, Chun;Geghman, Kindiya;Bogdanov, Mikhail;Przedborski, Serge;Beal, M. Flint;Burke, Robert E.;Li, Chenjian
通讯作者：
Li, Chenjian
影响因子：
1.7
作者：
Gandhi, Reno M.;Kogan, Cary S.;MacLeod, Lindsey S.
通讯作者：
MacLeod, Lindsey S.
影响因子：
3.5
作者：
Iaccarino, Ciro;Crosio, Claudia;Barone, Paolo
通讯作者：
Barone, Paolo
影响因子：
2
作者：
Jessberger, Sebastian;Clark, Robert E.;Gage, Fred H.
通讯作者：
Gage, Fred H.