The Mitochondrion-STING Axis in An Early Childhood Onset Neurodegenerative Disease

项目摘要 线粒体是细胞的发电站，通常被视为生活在细胞质中的细菌。强调 或受损的线粒体通过激活多种先天免疫信号通路诱导炎症 包括DNA传感cGAS-STING途径。我们最近发现，细胞质缺乏 去糖基化酶NGLY 1导致线粒体损伤和STING途径的有效激活。突变 NGLY 1基因的突变与儿童早期发病的神经退行性疾病有关， 也没有心理治疗我们最近建立了一个Ngly 1缺陷小鼠模型， 协调性和运动功能的发作和进行性恶化。我们还介绍了令人兴奋的分子和 遗传证据表明，在神经病理学中涉及的神经元-STING轴。本项目的总体目标 是定义NGLY 1缺陷的神经病理学机制，重点关注以下机制： 这是一个新的轴。目标1将通过遗传和单细胞方法定义细胞类型特异性。 目的2将剖析神经元和神经胶质细胞的细胞内信号通路。目标3将评估治疗方法 瞄准的是Bronzon-STING轴这里提出的研究应该揭示的核心机制， 神经病理学和神经退行性变中的突触-STING轴，这将在许多领域具有广泛的意义。 影响着数百万人的复杂的神经变性疾病。

PROJECT SUMMARY Mitochondria are powerhouses of the cell that are often viewed as bacteria living in the cytosol. Stressed or damaged mitochondria induce inflammation through activation of multiple innate immune signaling pathways including the DNA sensing cGAS-STING pathway. We recently showed that deficiency of a cytoplasmic deglycosylase NGLY1 results in mitochondrial damage and potent activation of the STING pathway. Mutations in the NGLY1 gene are associated with an early childhood onset neurodegenetive disease with high mortality and no therapy. We recently established and characterized a Ngly1-deficient mouse model that develop early onset and progressive deteriorating coordination and motor functions. We also present exciting molecular and genetic evidence that implicate the mitochondrion-STING axis in neuropathology. The overall goal of this project is to define the neuro-pathological mechanism of NGLY1-deficiency, with a strong focus on the mechanism of the mitochondrion-STING axis. Aim 1 will define cell type specificity through genetic and single-cell approaches. Aim 2 will dissect intracellular signaling pathways in neuronal and glial cells. Aim 3 will evaluate therapies targeting the mitochondrion-STING axis. Studies proposed here should reveal the central mechanism of the mitochondrion-STING axis in neuropathology and neurodegeneration, which will have broad implications in many complex neurogenerative diseases that are affecting millions of people.