Mechanisms of LRRK2 Mediated Neurotoxicity

LRRK2 介导的神经毒性机制

• 批准号: 10117999
• 负责人: Andrew B West
• 金额: $ 40.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117999
• 关键词: Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; American; Autopsy; Biological Models; Brain; Brain Diseases; Cells; Clinical; Complement; DNA Sequence Alteration; Data; Dementia; Disease; Disease Progression; Disease model; Dorsal; Future; Genes; Genetic; Hippocampus (Brain); Human; Human Genetics; Idiopathic Parkinson Disease; Immune; Impairment; Inflammation; Inflammatory Response; Injections; Knock-in; Knock-in Mouse; Knock-out; LRRK2 gene; Lead; Lewy Body Dementia; Lewy Body Disease; Link; Literature; Mediating; Mediation; Missense Mutation; Modeling; Morbidity - disease rate; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathologic; Pathology; Phosphotransferases; Proteins; Recombinants; Research Project Grants; Role; Series; Study models; Tauopathies; Testing; Therapeutic; Tissues; Transgenic Organisms; United States; Work; alpha synuclein; design; disorder control; experimental study; kinase inhibitor; mortality; mouse model; mutant; mutation carrier; neuroinflammation; neurotoxicity; novel; response; synuclein; targeted treatment; tau Proteins; tau interaction

Supplement for R01-NS064934 “Mechanisms of LRRK2 Neurotoxicity” Abstract- LRRK2 in tauopathy Parkinson's disease (PD) and related Lewy body diseases, including dementia with Lewy bodies (DLB), are common causes of Alzheimer's disease related dementias (ADRDs). Although therapies that might slow or halt disease have not been found, recent discoveries from human genetics, post-mortem tissue studies, and disease models have zeroed in on a few genes hypothesized to control disease progression. Tens of thousands of Americans harbor missense mutations in the LRRK2 gene that increase LRRK2 kinase activity and cause PD. Although LRRK2-linked disease is clinically indistinguishable from idiopathic PD, LRRK2 mutation carriers often demonstrate prominent Alzheimer's-type tau pathology, sometimes without traces of alpha-synuclein pathology, in vulnerable regions through the brain. In our ongoing efforts in this project to define the role of LRRK2 in neurodegeneration, we have identified critical interactions between LRRK2 and alpha-synuclein in both neurons and immune cells that both express LRRK2 protein. In this Supplement, we propose the exploration of a direct LRRK2-tau interaction in LRRK2 mediation of Alzheimer's type-tau inclusion spread and neuroinflammation. In supplement to our ongoing work, we will test whether LRRK2 kinase inhibition impairs tau inclusion formation and spread in the brain. In complement to kinase inhibition, we will determine whether LRRK2 kinase activation via genetic mutations in the LRRK2 gene promotes tau inclusions and deleterious pro-inflammatory responses. These studies will help us provide a framework to better understand whether a strong connection exists between LRRK2 and tau pathology found in Alzheimer's disease. Our work may lead to the consideration of tauopathies and Alzheimer's disease (AD) as novel indications for LRRK2-directed therapies.

R01-NS064934“LRRK2 神经毒性机制”的补充 摘要- tau蛋白病中的LRRK2 帕金森病（PD）和相关的路易体疾病，包括路易体痴呆（DLB）， 是阿尔茨海默病相关痴呆症 (ADRD) 的常见原因。尽管治疗可能会减缓或 人类遗传学、死后组织研究的最新发现以及 疾病模型将注意力集中在一些被认为可以控制疾病进展的基因上。数十个 数千名美国人的 LRRK2 基因存在错义突变，从而增加了 LRRK2 激酶活性 并引起PD。尽管 LRRK2 相关疾病在临床上与特发性 PD 无法区分，但 LRRK2 突变携带者通常表现出明显的阿尔茨海默病型 tau 病理学，有时没有任何迹象 α-突触核蛋白病理学，位于大脑的脆弱区域。 在这个项目中，我们不断努力定义 LRRK2 在神经退行性疾病中的作用，我们已经 确定了神经元和免疫细胞中 LRRK2 和 α-突触核蛋白之间的关键相互作用 表达LRRK2蛋白。在本补充中，我们建议探索 LRRK2-tau 的直接相互作用 LRRK2 介导阿尔茨海默病 tau 型包涵体扩散和神经炎症。作为对我们的补充 在正在进行的工作中，我们将测试 LRRK2 激酶抑制是否会损害 tau 包涵体的形成和扩散 脑。作为激酶抑制的补充，我们将确定 LRRK2 激酶是否通过遗传激活 LRRK2 基因突变会促进 tau 蛋白内含物和有害的促炎症反应。这些 研究将帮助我们提供一个框架，以更好地了解之间是否存在牢固的联系 阿尔茨海默病中发现 LRRK2 和 tau 病理学。我们的工作可能会导致人们考虑tau蛋白病 和阿尔茨海默病（AD）作为 LRRK2 导向疗法的新适应症。