The pathogenic LRRK2 R1441C mutation induces specific deficits modeling the prodromal phase of Parkinson's disease in the mouse
The pathogenic LRRK2 R1441C mutation induces specific deficits modeling the prodromal phase of Parkinson's disease in the mouse
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DOI：
10.1016/j.nbd.2017.05.013
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发表时间：
2017-09-01
影响因子：
6.1
通讯作者：
Wurst, W.
中科院分区：
文献类型：
--
作者：
Giesert, F.;Glasl, L.;Wurst, W.
本研究的目的是进一步探索富含亮氨酸重复激酶 2 (LRRK2) 基因的体内功能，该基因在某些家族性帕金森病 (PD) 中发生突变。我们构建了内源性小鼠 LRRK2 基因 GTPase 结构域（LRRK2 R1441C 系）中含有疾病相关点突变 R1441C 的小鼠模型，并与现有的 LRRK2 敲低系（LRRK2 敲低系）相比，对这些动物的整个生命周期进行了全面分析。这两个品系的动物在年轻或年老时都没有表现出严重的运动功能障碍或神经变性的病理体征。然而，在老年时，纯合 LRRK2 R1441C 动物表现出与 PD 前驱期相关的明显表型，例如精细运动任务、步态和嗅觉损伤。这些表型在 LRRK2 敲低动物中只能轻微观察到，可能是由于体外突触传递研究表明补偿机制的激活所致。因此，在生物体水平上，LRRK2 R1441C 突变并不表现为蛋白质功能丧失，而是诱导突变特异性缺陷。此外，根据所呈现的表型判断，LRRK2-R1441C 敲入系是 PD 前驱期的有效临床前模型。 (C) 2017 年，爱思唯尔公司出版
The aim of the present study was to further explore the in vivo function of the Leucine-rich repeat kinase 2 (LRRK2)-gene, which is mutated in certain familial forms of Parkinson's disease (PD). We generated a mouse model harboring the disease-associated point mutation R1441C in the GTPase domain of the endogenous murine LRRK2 gene (LRRK2 R1441C line) and performed a comprehensive analysis of these animals throughout lifespan in comparison with an existing knockdown line of LRRK2 (LRRK2 knockdown line). Animals of both lines do not exhibit severe motor dysfunction or pathological signs of neurodegeneration neither at young nor old age. However, at old age the homozygous LRRK2 R1441C animals exhibit clear phenotypes related to the prodromal phase of PD such as impairments in fine motor tasks, gait, and olfaction. These phenotypes are only marginally observable in the LRRK2 knockdown animals, possibly due to activation of compensatory mechanisms as suggested by in vitro studies of synaptic transmission. Thus, at the organismal level the LRRK2 R1441C mutation does not emerge as a loss of function of the protein, but induces mutation specific deficits. Furthermore, judged by the phenotypes presented, the LRRK2-R1441C knock-in line is a valid preclinical model for the prodromal phase of PD. (C) 2017 Published by Elsevier Inc.