Axonal Degeneration in LRRK2 Parkinson?s Disease

描述（由申请人提供）：帕金森病（PD）是第二常见的神经退行性疾病。富含亮氨酸重复序列激酶2（Leucine-rich-repeat-kinase 2，LRRK 2）是新近发现的PARK 8型PD的致病基因，具有常染色体显性遗传，是家族性和散发性PD中最常见的遗传原因。因此，了解LRRK 2介导的发病机制是重要的。我们已经产生了第一个LRRK 2转基因小鼠模型，该模型概括了PD的强大运动行为，神经化学和病理学特征。这些小鼠出现对左旋多巴治疗有反应的运动活动的年龄依赖性进行性降低。在病理学水平上，早期且最稳健的表型是黑质纹状体多巴胺能投射的轴突病，伴有过度磷酸化的tau蛋白。因此，在LRRK 2诱导的发病机制的所有方面中，tau介导的轴突变性是特别重要的，值得研究的主要努力。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，LRRK 2诱导tau蛋白过度磷酸化，介导致病作用。具体目的1：确认tau蛋白是突变型LRRK 2激酶信号传导的组成部分。假设2：在细胞水平，tau介导的轴突变性是LRRK 2 PD的关键方面。具体目的2：研究LRRK 2诱导的tau蛋白过度磷酸化是否会导致原代神经元细胞培养物中的轴突病理学。假设3.在生物体水平，tau介导的轴突病导致多巴胺能神经元变性和进行性运动缺陷。具体目的3：在遗传小鼠模型中测试tau和LRRK 2的相互作用。这组研究将确定LRRK 2发病机制中的分子和途径。这不仅从科学角度来看很重要，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。公共卫生相关性：帕金森病（PD）是第二大最常见的神经退行性疾病。富含亮氨酸重复序列激酶2（LRRK 2）的突变是PD最重要的遗传原因。因此，对LRRK 2致病机制的理解不仅从科学角度来看很重要，而且对于直接解决重大公共卫生问题的治疗开发也至关重要。

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.