R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations.
R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations.
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DOI：
10.1038/s42003-022-04136-8
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发表时间：
2022-11-10
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
--
作者：
LRRK2突变与帕金森病（PD）密切相关。汇聚的证据表明，LRRK2调节纹状体功能。在这里，通过使用基因敲入表达两种最常见的LRRK2致病突变G2019S和R1441C的小鼠品系，我们研究了LRRK2突变如何改变纹状体生理学。虽然我们发现R1441C和G2019S小鼠均显示黑质纹状体多巴胺释放减少，但仅在R1441C小鼠中观察到间接通路纹状体投射神经元的低兴奋性以及与受损的纹状体依赖性运动学习相关的改变。我们还发现，R1441C小鼠而不是G2019S小鼠中突触PKA活性的增加是R1441C小鼠运动学习障碍的特定改变的基础。总之，我们的数据表明，LRRK2突变对纹状体的影响不能简单地概括。相反，电化学，电生理，分子和行为水平的改变是不同的LRRK2突变。我们的研究结果为PD患者设计和优化治疗策略提供了机制见解。对两种表达LRRK2基因不同突变的小鼠模型（均与帕金森病相关）的研究揭示了电化学、电生理学、分子和行为水平的明显改变。
LRRK2 mutations are closely associated with Parkinson’s disease (PD). Convergent evidence suggests that LRRK2 regulates striatal function. Here, by using knock-in mouse lines expressing the two most common LRRK2 pathogenic mutations—G2019S and R1441C—we investigated how LRRK2 mutations altered striatal physiology. While we found that both R1441C and G2019S mice displayed reduced nigrostriatal dopamine release, hypoexcitability in indirect-pathway striatal projection neurons, and alterations associated with an impaired striatal-dependent motor learning were observed only in the R1441C mice. We also showed that increased synaptic PKA activities in the R1441C and not G2019S mice underlie the specific alterations in motor learning deficits in the R1441C mice. In summary, our data argue that LRRK2 mutations’ impact on the striatum cannot be simply generalized. Instead, alterations in electrochemical, electrophysiological, molecular, and behavioral levels were distinct between LRRK2 mutations. Our findings offer mechanistic insights for devising and optimizing treatment strategies for PD patients. Studies of two mouse models expressing different mutations of the LRRK2 gene, both associated with Parkinson’s disease, reveals distinct alterations at electrochemical, electrophysiological, molecular, and behavioral levels.
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影响因子：
11.2
作者：
Beeler, Jeff A.;Cao, Zhen Fang Huang;Kheirbek, Mazen A.;Ding, Yunmin;Koranda, Jessica;Murakami, Mari;Kang, Un Jung;Zhuang, Xiaoxi
通讯作者：
Zhuang, Xiaoxi
影响因子：
64.8
作者：
Cui, Guohong;Jun, Sang Beom;Jin, Xin;Pham, Michael D.;Vogel, Steven S.;Lovinger, David M.;Costa, Rui M.
通讯作者：
Costa, Rui M.
影响因子：
8.8
作者：
Beeler JA;Frank MJ;McDaid J;Alexander E;Turkson S;Bernardez Sarria MS;McGehee DS;Zhuang X
通讯作者：
Zhuang X
影响因子：
5.1
作者：
Chaturvedi P;Zhao B;Zimmerman DL;Belmont AS
通讯作者：
Belmont AS
影响因子：
5.3
作者：
Beccano-Kelly DA;Kuhlmann N;Tatarnikov I;Volta M;Munsie LN;Chou P;Cao LP;Han H;Tapia L;Farrer MJ;Milnerwood AJ
通讯作者：
Milnerwood AJ