Molecular regulation of LRRK2 in Parkinson's disease

帕金森病中 LRRK2 的分子调控

• 批准号: 10308145
• 负责人: Yulan Xiong
• 金额: $ 35.88万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308145
• 关键词: Affect; Age; Alzheimer' s Disease; Attention; Behavior; Behavioral; Biology; Cell physiology; Complex; Corpus striatum structure; Data; Defect; Dimerization; Disease; Disease Progression; Drosophila genus; Drug Targeting; Future; GTP Binding; GTPase-Activating Proteins; Genetic; Goals; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; In Vitro; Intervention; Investigation; Knowledge; LRRK2 gene; Link; Membrane; Molecular; Monitor; Movement Disorders; Mus; Mutation; Neurons; Nucleotides; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Pattern; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Physiological; Play; Population; Proteins; Regulation; Role; Substantia nigra structure; Symptoms; Testing; Therapeutic; United States; United States National Institutes of Health; age related neurodegeneration; base; behavior test; behavioral phenotyping; disease-causing mutation; dopaminergic neuron; guanine nucleotide binding protein; in vivo; interest; kinase inhibitor; neurotoxicity; new therapeutic target; nigrostriatal pathway; novel; pars compacta; targeted treatment; therapeutic development

Parkinson's disease (PD) is recognized as the most common movement disorder. The cardinal symptoms of PD are caused by the progressive degeneration of dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc) and accompanying striatal pathology. Mutations in LRRK2 are known to be the most common genetic causes of PD. Given its strong genetic links and compelling drug ability, LRRK2 represents a clear target for therapeutic development. However, the mechanisms that regulate LRRK2 function remain unclear. Moreover, LRRK2 regulation in striatal pathology and striatal-dependent behaviors remains largely elusive despite high expression of LRRK2 in the striatum. The LRRK2 protein includes two important enzymatic domains: a ROC (Ras of Complex) GTPase domain and a kinase domain. Disease causing mutations are found in both GTPase and kinase domains, indicating the importance of both GTPase and kinase activities of LRRK2. To date studies have focused largely on the kinase activity of LRRK2 while attention on the GTPase domain is limited. LRRK2 is a guanine nucleotide-binding protein, but the mechanism of direct regulation of its GTPase domain is unclear. Conventional guanine nucleotide-binding proteins are typically regulated by GTPase-activating proteins (GAPs) and guanine nucleotide-exchange factors (GEFs). Some guanine nucleotide-binding proteins can be activated by nucleotide-dependent dimerization (GAD). Whether LRRK2 is regulated by GAPs and GEFs or by GAD has been actively investigated. We have previously identified the first GAP ArfGAP1 for LRRK2 in vitro and in vivo. Recently we discovered a potential physiological GEF for LRRK2. It has similar expression patterns with LRRK2 in nigrostriatal pathway, interacts with LRRK2 and regulates LRRK2 neurotoxicity. Based on the preliminary observations, our central hypothesis is that this GEF serves as a physiological GEF for LRRK2 to increase LRRK2 GTP binding activity, regulate LRRK2 cellular function and LRRK2-induced striatal pathology and related behavioral deficits. The objective of this study is (1) to identify and characterize the first physiological GEF for LRRK2, (2) to determine how this GEF regulates LRRK2 function, and (3) to explore the regulation of this GEF on LRRK2 in striatal pathology and related behavior. Accomplishment of this study will lead to understanding how the GTPase function of LRRK2 is regulated and to determining whether this regulation affects the actions of LRRK2 in striatum. The LRRK2 GTPase, GAP or GEF activities would be served as new therapeutic targets, which is distinct from direct kinase inhibition of LRRK2. New knowledge regarding this aspect of LRRK2 biology will advance our understanding of the physiologic and pathophysiologic actions of LRRK2 as well as potential identification of novel targets for future pharmacologic intervention.

帕金森病（Parkinson's disease，PD）是最常见的运动障碍。主要症状 的PD是由黑质部多巴胺能（DA）神经元的进行性变性引起的 黑质纤维化（SNpc）和伴随的纹状体病理学。已知LRRK 2中的突变是最常见的 PD的常见遗传原因鉴于其强大的遗传联系和令人信服的药物能力，LRRK 2代表了一种新的治疗方法。 明确治疗发展目标。然而，调节LRRK 2功能的机制仍然存在， 不清楚此外，LRRK 2在纹状体病理学和纹状体依赖性行为中的调节在很大程度上仍然存在。 尽管LRRK 2在纹状体中高表达，但难以实现。LRRK 2蛋白包括两个重要的 酶结构域：ROC（复合物的Ras）GT酶结构域和激酶结构域。致病 在GT3和激酶结构域中都发现了突变，表明GT3和激酶结构域的重要性。 LRRK 2的激酶活性。迄今为止，研究主要集中在LRRK 2的激酶活性上， 对GTTR域的关注是有限的。LRRK 2是一种鸟嘌呤核苷酸结合蛋白，但其机制 其GTdR结构域的直接调控尚不清楚。常规的鸟嘌呤核苷酸结合蛋白是 通常由GTP酶激活蛋白（GAP）和鸟嘌呤核苷酸交换因子（GEF）调节。 一些鸟嘌呤核苷酸结合蛋白可以通过核苷酸依赖性二聚化（GAD）激活。 LRRK 2是否受到GAP和GEF或GAD的调节已被积极研究。我们有 先前在体外和体内鉴定了LRRK 2的第一个GAP ArfGAP 1。最近我们发现了一种潜在的 LRRK 2的生理GEF。在黑质纹状体通路中与LRRK 2具有相似的表达模式， 与LRRK 2结合并调节LRRK 2神经毒性。根据初步观察，我们的中心假设 该GEF作为LRRK 2的生理GEF，以增加LRRK 2 GTP结合活性，调节LRRK 2的GTP结合活性， LRRK 2细胞功能和LRRK 2诱导的纹状体病理学和相关行为缺陷。的目标 这项研究是（1）确定和表征LRRK 2的第一个生理GEF，（2）确定这种GEF是如何产生的， GEF对LRRK 2功能的调节;（3）探讨该GEF在纹状体病理中对LRRK 2的调节作用 相关行为。本研究的完成将有助于了解GTdR的功能， LRRK 2受调控，并确定这种调控是否影响LRRK 2在纹状体中的作用。的 LRRK 2 GT3、GAP或GEF活性将作为新的治疗靶点，这与 LRRK 2的直接激酶抑制。关于LRRK 2生物学这方面的新知识将推动我们的研究。 了解LRRK 2的生理和病理生理作用以及潜在的识别 未来药物干预的新靶点。