Mechanisms of LRRK2 Mediated Neurotoxicity

LRRK2 介导的神经毒性机制

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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的补充“ LRRK2神经毒性的机制” 摘要 - lrrk2在tauopathy中帕金森氏病（PD）和相关的路易体疾病，包括痴呆症患有路易的身体（DLB），是阿尔茨海默氏病有关的痴呆症（ADRDS）的常见原因。虽然疗法可能会放慢或尚未发现停止疾病，人类遗传学，死后组织研究和疾病模型已归因于一些假设可以控制疾病进展的基因。数十个 LRRK2基因中的成千上万的美国人藏有识别突变，以增加LRRK2激酶活性尽管LRK2连接疾病在临床上与特发性PD没有区别，但LRRK2在临床上没有区别突变载体通常表现出突出的阿尔茨海默氏症型tau病理学，有时没有痕迹通过大脑的脆弱区域中的α-核蛋白病理学。在我们为定义LRRK2在神经变性中的作用的持续努力中，我们有确定了在神经元和免疫细胞中LRRK2和α-突触核蛋白之间的临界相互作用 Express LRRK2蛋白。在这种补充中，我们提出了对直接LRK2-TAU相互作用的探索 lrrk2阿尔茨海默氏症的type-tau纳入扩散和神经炎症的介导。补充我们正在进行的工作，我们将测试LRRK2激酶抑制是否会损害tau的纳入形成并扩散脑。在完成激酶抑制后，我们将确定LRRK2激酶是否通过遗传激活 LRRK2基因中的突变促进tau夹杂物和有害的促炎反应。这些研究将帮助我们提供一个框架，以更好地了解在阿尔茨海默氏病中发现的LRRK2和Tau病理学。我们的工作可能会导致对tauopathies的考虑和阿尔茨海默氏病（AD）作为LRRK2定向疗法的新颖适应症。