Differences in Stability, Activity and Mutation Effects Between Human and Mouse Leucine-Rich Repeat Kinase 2.
Differences in Stability, Activity and Mutation Effects Between Human and Mouse Leucine-Rich Repeat Kinase 2.
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DOI：
10.1007/s11064-018-2650-4
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发表时间：
2019-06
影响因子：
4.4
通讯作者：
Cookson MR
中科院分区：
文献类型：
--
作者：
Langston RG;Rudenko IN;Kumaran R;Hauser DN;Kaganovich A;Ponce LB;Mamais A;Ndukwe K;Dillman AA;Al-Saif AM;Beilina A;Cookson MR
富含亮氨酸重复序列激酶2（LRRK2）基因突变与帕金森病（PD）的发病机制有关。PD相关LRRK2突变的鉴定导致了新型动物模型的开发，主要是在小鼠中。然而，人LRRK2和小鼠Lrrk2蛋白的特征以前没有被直接比较。在这里，我们表明，来自不同物种的蛋白质具有不同的生化特性，与人类直系同源物相比，小鼠蛋白质更稳定，但激酶活性显着降低。在研究PD相关突变和风险因素对蛋白质功能的影响时，我们发现保守取代（如G2019S）对人类和小鼠LRRK2蛋白的影响相似，但在人类和小鼠之间不完全保守的位置2385周围的变异诱导了不同的体外行为。总的来说，我们的研究结果表明，人类和小鼠LRRK2之间的结构差异可能是我们观察到的这两种LRRK2蛋白质的不同性质的原因。这些结果对小鼠LRRK2突变的疾病建模和动物药理学治疗的测试具有影响。
Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene have been implicated in the pathogenesis of Parkinson’s disease (PD). Identification of PD-associated LRRK2 mutations has led to the development of novel animal models, primarily in mice. However, the characteristics of human LRRK2 and mouse Lrrk2 protein have not previously been directly compared. Here we show that proteins from different species have different biochemical properties, with the mouse protein being more stable but having significantly lower kinase activity compared to the human orthologue. In examining the effects of PD-associated mutations and risk factors on protein function, we found that conserved substitutions such as G2019S affect human and mouse LRRK2 proteins similarly, but variation around position 2385, which is not fully conserved between humans and mice, induces divergent in vitro behavior. Overall our results indicate that structural differences between human and mouse LRRK2 are likely responsible for the different properties we have observed for these two species of LRRK2 protein. These results have implications for disease modelling of LRRK2 mutations in mice and on the testing of pharmacological therapies in animals.
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DOI：
10.1073/pnas.1318306111
发表时间：
2014-02-18
影响因子：
11.1
作者：
Beilina, Alexandria;Rudenko, Iakov N.;Cookson, Mark R.
通讯作者：
Cookson, Mark R.
影响因子：
3.7
作者：
Li, Tianxia;He, Xinhua;Smith, Wanli W.
通讯作者：
Smith, Wanli W.
影响因子：
4.8
作者：
Greggio, Elisa;Zambrano, Ibardo;Cookson, Mark R.
通讯作者：
Cookson, Mark R.
影响因子：
2.9
作者：
Ito, Genta;Okai, Takuro;Iwatsubo, Takeshi
通讯作者：
Iwatsubo, Takeshi
DOI：
10.1073/pnas.0507360102
发表时间：
2005-11-15
影响因子：
11.1
作者：
West, AB;Moore, DJ;Dawson, TM
通讯作者：
Dawson, TM