Mechanisms of LRRK2 Mediated Neurotoxicity

对R01-NS064934《LRRK2神经毒性机制》的补充 肌萎缩侧索硬化症中的LRRK2 帕金森氏病(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(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 疾病模型已经将重点放在了几个假想的控制疾病进展的基因上。几十个 数以千计的美国人存在LRRK2基因的错义突变，这种突变会增加LRRK2激酶的活性 导致警局。虽然LRRK2相关疾病在临床上与特发性帕金森病无法区分，但LRRK2 突变携带者通常表现出明显的阿尔茨海默氏型tau病变，有时没有迹象表明 阿尔法-突触核蛋白病理，通过大脑的脆弱区域。 在我们正在进行的确定LRRK2在神经退行性变中的作用的项目中，我们有 在神经元和免疫细胞中发现LRRK2和α-突触核蛋白之间的关键相互作用 表达LRRK2蛋白。在这份补充材料中，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包涵体扩散和神经炎症。作为我们的补充 ，我们将测试抑制LRRK2是否会损害tau包涵体的形成和在 大脑。作为对激酶抑制的补充，我们将确定LRRK2激酶是否通过基因激活 LRRK2基因突变促进tau包涵体和有害的促炎反应。这些 研究将帮助我们提供一个框架，以更好地了解 阿尔茨海默病中发现LRRK2和tau病理。我们的工作可能会导致对表象疗法的考虑 和阿尔茨海默病(AD)作为LRRK2指导治疗的新适应症。

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.