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

项目总结 线粒体是细胞的动力源，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个先天免疫信号通路而引发炎症 包括DNA感知的cGAS-STING通路。我们最近发现了一种细胞质缺陷 脱糖酶NGLY1导致线粒体损伤和刺痛通路的有效激活。突变 NGLY1基因与儿童早期发病的高死亡率神经退行性疾病有关 也不需要治疗。我们最近建立并鉴定了一种早期发育的Nly1缺陷小鼠模型 开始和进行性的协调和运动功能恶化。我们还介绍了令人兴奋的分子和 在神经病理学中涉及线粒体刺轴的遗传证据。这个项目的总体目标是 旨在明确NGLY1缺乏症的神经病理机制，重点探讨NGLY1缺乏症的发病机制 线粒体刺轴。目标1将通过遗传和单细胞方法定义细胞类型特异性。 目标2将剖析神经细胞和神经胶质细胞的细胞内信号通路。AIM 3将评估治疗方法 瞄准线粒体刺轴。这里提出的研究应该揭示出 线粒体刺轴在神经病理和神经退行性变中的作用，这将在许多方面具有广泛的意义 正在影响数百万人的复杂的神经生成性疾病。

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.