Axonal Degeneration in LRRK2 Parkinson?s Disease

描述(申请人提供)：帕金森病(PD)是第二种最常见的神经退行性疾病。新发现的Park8型PD常染色体显性遗传致病基因亮氨酸重复序列2(LRRK2)的突变是家族性和散发性PD最常见的遗传原因。因此，了解LRRK2介导的致病机制具有重要意义。我们已经建立了第一个LRRK2转基因小鼠模型，该模型概括了帕金森病强大的运动行为、神经化学和病理特征。这些小鼠对左旋多巴的治疗有反应，表现为与年龄相关的渐进性运动减少。在病理学水平上，早期和最强健的表型是黑质纹状体多巴胺能投射的轴索病变，伴有过度磷酸化的tau。因此，在LRRK2诱导的多种致病机制中，tau介导的轴突变性尤为重要，值得深入研究。我们将在分子、细胞和动物模型水平上解决重要问题。假设1：在分子水平上，LRRK2诱导tau过度磷酸化，介导致病效应。具体目的1：证实tau是突变的LRRK2信号通路的一个组成部分。假设2：在细胞水平上，tau介导的轴突变性是LRRK2PD的一个关键方面。具体目的2：研究LRRK2诱导的tau过度磷酸化是否导致原代培养神经元细胞的轴突病理改变。假设3：在机体水平上，tau介导的轴索病变导致多巴胺能神经元变性和进行性运动障碍。具体目标3：在遗传小鼠模型中测试tau和LRRK2的相互作用。这组研究将确定LRRK2发病机制中的分子和途径。这不仅从科学角度来说很重要，而且对于直接解决重大公共卫生问题的治疗发展也至关重要。公共卫生意义：帕金森病(PD)是第二种最常见的神经退行性疾病。富含亮氨酸的重复蛋白激酶2(LRRK2)基因突变是帕金森病最重要的遗传原因。因此，对LRRK2致病机制的了解不仅从科学角度来说是重要的，而且对于直接解决重大公共卫生问题的治疗开发也是至关重要的。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the second most common neurodegenerative disease. Mutations in Leucine-rich-repeat-kinase 2 (LRRK2), the newly identified causative gene for PARK8 type PD with autosomal dominant inheritance, are the most prevalent genetic causes in both familial and sporadic PD. Therefore it is important to understand the mechanisms of LRRK2 mediated pathogenesis. We have generated the first transgenic mouse model for LRRK2 that recapitulated robust motor behavioral, neurochemical and pathological features of PD. These mice develop an age-dependent progressive decrease in motor activity that is responsive to treatment with levodopa. At the level of pathology, the early and most robust phenotype is the axonopathy of the nigrostriatal dopaminergic projection, accompanied by hyperphosphorylated tau. Therefore, among all the aspects of LRRK2 induced pathogenesis, the tau-mediated axonal degeneration is particularly important and worth a major effort of investigation. We will address important questions at molecular, cellular and animal model levels. Hypothesis 1: At the molecular level, LRRK2 induces tau hyperphosphorylation that mediates the pathogenic effects. Specific Aim 1: To confirm that tau is an integral component of mutant LRRK2 kinase signaling. Hypothesis 2: At the cellular level, tau mediated axonal degeneration is a critical aspect of LRRK2 PD. Specific Aim 2: To investigate whether LRRK2-induced tau hyperphosphorylation causes axonal pathology in primary neuronal cell cultures. Hypothesis 3. At the organismal level, tau-mediated axonopathy leads to dopaminergic neuronal degeneration and progressive motor deficits. Specifc Aim 3: To test the interaction of tau and LRRK2 in genetic mouse models. This set of studies will identify the molecules and the pathways in LRRK2 pathogenesis. This is not only important from a scientific point, but also critical for the therapeutic development that directly addresses a major public health issue. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is the second most common neurodegenerative disease. Mutations in Leucine-rich-repeat-kinase 2 (LRRK2) are the most important genetic causes in PD. Therefore the understanding of the LRRK2 pathogenic mechanisms is not only important from a scientific point, but also critical for the therapeutic development that directly addresses a major public health issue.