Functional Characterization of LRRK2 Knock-out and Knock-in Mouse Models

描述（由申请人提供）：帕金森病（PD）是一种与年龄相关的多因素疾病，由遗传和环境因素共同引起。编码富含亮氨酸重复序列激酶2（LRRK2）的基因突变是常染色体显性帕金森综合征最常见的遗传原因。在某些人群中，LRRK2突变的频率占家族性PD病例的30%，G2019S是最常见的突变。LRRK2突变也在一些散发性帕金森综合征患者中发现。自LRRK2的第一个突变被发现以来已经过去了四年，但Lrrk2的功能以及突变如何导致PD仍然在很大程度上未知。为了深入了解突变的病理机制，我们建立了LRRK2敲除和Lrrk2 G2019S敲入小鼠模型。这些模型代表了评估Lrrk2的正常和生理作用的优秀生理测试系统。我们将描述这些小鼠的神经元脆弱性，神经退行性改变，多巴胺释放和行为改变，这些表型都与Lrrk2功能有关。这项工作将大大有助于我们理解Lrrk2的功能作用，并指导未来的研究和治疗设计。 公共卫生相关性：LRRK2基因突变导致帕金森病。该提案旨在使用动物模型来研究LRRK2突变发挥其致病作用的生物学方式。

DESCRIPTION (provided by applicant): Parkinson disease (PD) is an age-associated multi-factorial disorder resulting from a combination of genetic and environmental factors. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most frequent genetic cause of autosomal dominant Parkinsonism. In some populations, the frequency of LRRK2 mutations accounts for as much as 30% of familial PD cases, with G2019S being the most frequent mutation. LRRK2 mutations are also found in some sporadic Parkinsonism patients. Four years have passed since the first mutations in LRRK2 were identified, but the function of Lrrk2 and how mutations lead to PD remains largely unknown. To gain insight into the pathologic mechanisms of the mutations, we have created LRRK2 knock-out and Lrrk2 G2019S knock-in mouse models. These models represent excellent physiological test systems to evaluate the normal and physiological roles of Lrrk2. We will characterize these mice for neuronal vulnerability, neurodegenerative alterations, dopamine release and behavioral alterations, phenotypes that have all been linked to Lrrk2 function. This work should significantly contribute to our understanding of the functional role of Lrrk2 and direct future studies and therapeutic design. PUBLIC HEALTH RELEVANCE: Mutations in the gene LRRK2 cause Parkinson Disease. This proposal aims to use animal models to study the biological manner in which LRRK2 mutations exert their pathogenic effects.