Resolving the Role of Neuronal STING in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

项目概述：干扰素基因刺激因子（STING）通路负责感应DNA 损伤和激活先天免疫反应作为宿主病原体防御程序的一部分。 尽管STING与几种神经退行性疾病有关，但其作用被认为是 通过骨髓细胞介导，并且神经元内STING激活的潜力尚未被证实。 探讨了该提案的主要目标是确定神经元STING在神经变性中的作用 和痴呆使用肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）， DNA损伤的反应。我们将重点关注C9 orf 72基因中的内含子六核苷酸重复， 这是ALS和FTD最常见的家族性原因，TDP-43聚集在 几乎所有的ALS病例和大约一半的FTD病例。总的模型是DNA损伤， 由C9 orf 72二肽以及TDP-43功能障碍引起的STING，导致神经元中的STING激活。 我们的初步数据呈现了人C9 orf 72中神经元STING增加的一致图片。 脑，小鼠C9 orf 72模型，和人诱导多能干细胞（iPSC）衍生的神经元， ALS患者。我们将确定STING增加的区域特异性以及它如何与 神经变性、DNA损伤和其他C9 orf 72和TDP-43疾病特征。测试 为了确定神经元中STING的结果，我们将使用基于AAV的C9 orf 72疾病模型并确定 STING的神经元特异性敲除是否会影响神经变性以及效果如何比较 STING的整体敲除或小胶质细胞内的敲除。使用iPSC衍生的和原代小鼠 神经元，我们将确定STING激活的机制，以及激活如何与下游神经元联系在一起。 脆弱神经元亚型内的调节剂。我们还将评估在多大程度上阻止或 敲低STING保护神经元免受体外疾病机制模型的影响。成功 该项目的完成为验证治疗干预的具体目标奠定了基础， 评估作为疾病生物标志物的关键途径成分，并研究STING途径， 其他神经退行性疾病和痴呆症。

Project Summary: The stimulator of interferon genes (STING) pathway is responsible for sensing DNA damage and activating the innate immune response as part of a host pathogen defense program. Although STING has been implicated in several neurodegenerative diseases, the effect has thought to be mediated through myeloid cells, and the potential for STING activation within neurons has been not explored. The main goal of this proposal is to define the role of neuronal STING in neurodegeneration and dementia using amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in response to DNA damage. We will focus on the intronic hexanucleotide repeat in the C9orf72 gene, which is the most common familial cause of both ALS and FTD, and TDP-43, which aggregates in almost all ALS cases and about half of FTD. The overall model is that DNA damage, which can be caused by C9orf72 dipeptides as well as TDP-43 dysfunction, leads to STING activation in neurons. Our preliminary data present a concordant picture of increased neuronal STING in human C9orf72 brains, mouse C9orf72 models, and human induced pluripotent stem cell (iPSC)-derived neurons from ALS individuals. We will determine the regional specificity of STING increase and how it correlates with neurodegeneration, DNA damage, and other C9orf72 and TDP-43 disease features. To test the consequence of STING in neurons, we will use an AAV-based C9orf72 disease model and determine whether neuronal-specific knockout of STING affects neurodegeneration and how the effect compares to global knockout of STING or knockout within microglia. Using iPSC-derived and primary mouse neurons, we will determine mechanisms of STING activation, and how activation ties to downstream modulators within vulnerable neuronal subtypes. We will also assess to what extent blocking or knocking down STING protects neurons against disease mechanistic models in vitro. The successful completion of the project sets the stage for validating specific targets for therapeutic intervention, evaluating key pathway components as disease biomarkers, and investigating STING pathways in other neurodegenerative diseases and dementias.