LRRK2 modulates the progression of neuropathology in a mouse model of tauopathy

LRRK2 调节 tau 蛋白病小鼠模型中神经病理学的进展

基本信息

批准号：
8556206
负责人：
Rachel M Bailey
金额：
$ 0.91万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-21 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8556206
关键词：
Address Affect Binding Binding Proteins Biological Cell Culture System Cell Culture Techniques Cells Cultured Cells Data Development Disease Disease Progression Environmental Risk Factor Etiology Exhibits Future Genes Genetic Risk Goals Haplotypes Harvest Human In Vitro Link Measures Mediating Microtubules Modeling Mus Mutate Mutation Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Parkinson Disease Pathogenesis Pathology Patients Phosphorylation Phosphotransferases Progressive Supranuclear Palsy Proteins Publishing Reporting Research Risk Factors Site Tauopathies Testing Time Tissues Toxic effect Transgenic Mice Tubulin Work abnormally phosphorylated tau brain tissue corticobasal degeneration gain of function in vitro activity in vivo interest leucine-rich repeat kinase 2 meetings mouse LRRK2 protein mouse model mutant neuron loss neuropathology neurotoxicity novel overexpression research study tau Proteins tau aggregation tau function tau interaction tau phosphorylation tau-1 tau-protein kinase therapeutic development

项目摘要

DESCRIPTION (provided by applicant): The link between tau, a microtubule binding protein whose function is regulated by phosphorylation, and the pathogenesis of Parkinson's disease (PD) remains unclear. In view of this, it is interesting that mutations in the gene encoding Leucine-rich repeat kinase 2 (LRRK2), which are a major risk factor for PD, have been associated with pathologies that include tau tangles and aberrant tau phosphorylation. The most common mutation, G2019S, is within the kinase domain of LRRK2 and shows increased kinase activity in vitro, which is proposed to mediate its cellular toxicity. The normal function of LRRK2 and how mutations affect this function to affect disease pathogenesis is unknown. Tau has recently been shown to be phosphorylated by LRRK2, but it is still not known if LRRK2 and tau interact in vivo and how this interaction is altered by mutations in LRRK2 to affect aggregation and cause disease. The overall objectives of this application are to determine if LRRK2 modulates tau pathology and to identify the mechanism(s) by which this occurs. This proposal will use a combination of in vitro and in vivo approaches to identify mechanisms by which tau phosphorylation and aggregation are altered by wild-type (WT) and mutant LRRK2 and determine how this affects neurotoxicity. Experiments under Aim 1 will determine how tau phosphorylation and aggregation are altered by WT and mutant LRRK2 in vitro and in cell culture systems. Preliminary data has confirmed that tau is a good substrate for LRRK2 kinase activity and has identified multiple sites that are phosphorylated by tau in vitro. The effects of LRRK2 phosphorylation at these sites on the development of tau aggregates will be examined using tau inclusion formation in vitro and in cultured cells. The biological relevance of data generated in Aim 1 will be tested by studies under Aim 2 of this proposal that will determine how WT and mutant LRRK2 modulate tauopathy in novel mouse models. WT and G2019S LRRK2 mice will be crossed with the rTg4510 mouse model of tauopathy, which has a well-characterized disease course of tauopathy. Tau phosphorylation, aggregation and neurotoxicity will be measured in tissue from these mice. Preliminary data show that WT LRRK2/rTg4510 have increased tau phosphorylation at specific sites and increased tau aggregation, supporting the use of these models in this proposal. Results from these studies are essential to understanding PD etiology and directing future research to identify mechanisms of LRRK2-mediated tau pathogenesis.

描述（由申请人提供）：Tau之间的联系，一种微管结合蛋白，其功能受磷酸化调节，帕金森氏病（PD）的发病机理仍不清楚。鉴于这一点，有趣的是，编码富含亮氨酸的重复激酶2（LRRK2）的基因中的突变是PD的主要危险因素，与包括Tau Tangles和异常TAU磷酸化的病理有关。最常见的突变G2019S在LRRK2的激酶结构域内，体外显示了激酶活性的增加，该激酶的活性提议介导其细胞毒性。 LRRK2的正常功能突变如何影响该功能影响疾病发病机理，尚不清楚。最近已显示tau被LRRK2磷酸化，但尚不清楚LRRK2和Tau在体内是否相互作用，以及如何通过LRRK2突变改变这种相互作用以影响聚集并引起疾病。本应用程序的总体目标是确定LRRK2是否调节TAU病理并确定发生这种情况的机制。该建议将使用体外和体内方法的组合来识别野生型（WT）和突变体LRRK2改变Tau磷酸化和聚集的机制，并确定这如何影响神经毒性。 AIM 1下的实验将确定WT和突变体LRRK2在体外和细胞培养系统中如何改变Tau磷酸化和聚集。初步数据已经证实，tau是LRRK2激酶活性的良好底物，并且已经鉴定出多个在体外磷酸化的位点。 LRRK2磷酸化在这些位点的影响对TAU聚集体发展的影响将在体外和培养细胞中使用TAU包容性形成。 AIM 1中产生的数据的生物学相关性将通过该提案的AIM 2的研究测试，该研究将决定WT和突变的LRRK2如何调节新型小鼠模型中的tauopathy。 WT和G2019S LRRK2小鼠将与tauopathy的RTG4510小鼠模型交叉，该模型具有特征性的tauopathy病程。 TAU磷酸化，聚集和神经毒性将在这些小鼠的组织中测量。初步数据表明，WT LRK2/RTG4510在特定位点增加了Tau磷酸化并增加了Tau聚集，从而在该建议中支持了这些模型的使用。这些研究的结果对于理解PD病因并指导未来的研究至关重要，以确定LRRK2介导的Tau发病机理的机制。