Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Developmental Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany; Technische Universität München-Weihenstephan, Lehrstuhl für Entwicklungsgenetik, c/o Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Developmental Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
Neurobiol Dis. 2017 Sep;105:179-193. doi: 10.1016/j.nbd.2017.05.013. Epub 2017 May 31.
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.
本研究旨在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。我们构建了一种携带内源性小鼠 LRRK2 基因 GTPase 结构域中与疾病相关的点突变 R1441C 的小鼠模型（LRRK2 R1441C 系），并与现有的 LRRK2 敲低系（LRRK2 敲低系）进行了全面的比较分析。在整个生命周期中，这两个系的动物既没有表现出严重的运动功能障碍，也没有表现出神经退行性病变的病理迹象，无论是在幼年还是老年。然而，在老年时，纯合的 LRRK2 R1441C 动物表现出与 PD 前驱期相关的明显表型，如精细运动任务、步态和嗅觉受损。这些表型在 LRRK2 敲低动物中仅略微可见，这可能是由于突触传递的体外研究表明存在代偿机制。因此，在机体水平上，LRRK2 R1441C 突变不是蛋白质的功能丧失，而是诱导突变特异性缺陷。此外，从呈现的表型来看，LRRK2-R1441C 敲入系是 PD 前驱期的有效临床前模型。
