Axonal Degeneration in LRRK2 Parkinson?s Disease

LRRK2 帕金森病中的轴突变性

• 批准号: 7698560
• 负责人: CHENJIAN LI
• 金额: $ 42.25万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7698560
• 关键词: Address; Animal Model; Antibodies; Behavioral; Biological Assay; Cell Culture Techniques; Complex; Corpus striatum structure; Cyclic AMP-Dependent Protein Kinases; Cyclin-Dependent Kinases; Data; Dopamine; Event; Fluorescence Resonance Energy Transfer; Gel; Genetic; Glycogen Synthase Kinase 3; In Vitro; Investigation; Levodopa; Mass Spectrum Analysis; Mediating; Methods; Midbrain structure; Mitogen Activated Protein Kinase 1; Molecular; Motor; Motor Activity; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; PARK8 gene; Parents; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Peptidylprolyl Isomerase; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphotransferases; Protein Kinase; Proteins; Public Health; Sampling; Signal Transduction; Tauopathies; Testing; Tissues; Transgenic Mice; Tubulin; age related; axonal degeneration; axonopathy; gain of function; histone deacetylase 6; hyperphosphorylated tau; leucine-rich repeat kinase 2; motor deficit; mouse LRRK2 protein; mouse model; mutant; neurochemistry; parent grant; protein complex; public health relevance; research study; tau Proteins; tau interaction; tau-1; tau-tubulin kinase; therapeutic development; tool

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.

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。富含亮氨酸重复激酶 2 (LRRK2) 的突变是新发现的常染色体显性遗传 PARK8 型帕金森病的致病基因，是家族性和散发性帕金森病最常见的遗传原因。因此，了解 LRRK2 介导的发病机制非常重要。我们已经为 LRRK2 构建了第一个转基因小鼠模型，该模型概括了 PD 的强大运动行为、神经化学和病理特征。这些小鼠的运动活动会随着年龄的增长而逐渐减少，这对左旋多巴治疗有反应。在病理学水平上，早期和最强烈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LRRK2诱导的发病机制的各个方面中，tau介导的轴突变性尤为重要，值得大力研究。我们将解决分子、细胞和动物模型水平上的重要问题。假设 1：在分子水平上，LRRK2 诱导 tau 蛋白过度磷酸化，从而介导致病作用。具体目标 1：确认 tau 是突变型 LRRK2 激酶信号传导的一个组成部分。假设 2：在细胞水平上，tau 介导的轴突变性是 LRRK2 PD 的一个关键方面。具体目标 2：研究 LRRK2 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。假设 3：在机体水平上，tau 介导的轴突病变导致多巴胺能神经元变性和进行性运动缺陷。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看很重要，而且对于直接解决重大公共卫生问题的治疗方法的开发也至关重要。公共卫生相关性：帕金森病 (PD) 是第二常见的神经退行性疾病。富含亮氨酸重复激酶 2 (LRRK2) 的突变是帕金森病最重要的遗传原因。因此，了解 LRRK2 致病机制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。