Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Changchun, China.
Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Changchun, China; Department of Neurobiology, Care Sciences & Society, Karolinska Institute, Karolinska University Hospital Solna, Stockholm, Sweden.
Neurobiol Dis. 2024 Nov;202:106710. doi: 10.1016/j.nbd.2024.106710. Epub 2024 Oct 28.
Neurodegenerative diseases (NDs) are a type of common chronic progressive disorders characterized by progressive damage to specific cell populations in the nervous system, ultimately leading to disability or death. Effective treatments for these diseases are still lacking, due to a limited understanding of their pathogeneses, which involve multiple cellular and molecular pathways. The triggering of an immune response is a common feature in neurodegenerative disorders. A critical challenge is the intricate interplay between neuroinflammation, neurodegeneration, and immune responses, which are not yet fully characterized. In recent years, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway, a crucial immune response for intracellular DNA sensing, has gradually gained attention. However, the specific roles of this pathway within cellular types such as immune cells, glial and neuronal cells, and its contribution to ND pathogenesis, remain not fully elucidated. In this review, we systematically explore how the cGAS-STING signaling links various cell types with related cellular effector pathways under the context of NDs for multifaceted therapeutic directions. We emphasize the discovery of condition-dependent cellular heterogeneity in the cGAS-STING pathway, which is integral for understanding the diverse cellular responses and potential therapeutic targets. Additionally, we review the pathogenic role of cGAS-STING activation in Parkinson's disease, ataxia-telangiectasia, and amyotrophic lateral sclerosis. We focus on the complex bidirectional roles of the cGAS-STING pathway in Alzheimer's disease, Huntington's disease, and multiple sclerosis, revealing their double-edged nature in disease progression. The objective of this review is to elucidate the pivotal role of the cGAS-STING pathway in ND pathogenesis and catalyze new insights for facilitating the development of novel therapeutic strategies.
神经退行性疾病（NDs）是一类常见的慢性进行性疾病，其特征是神经系统中特定细胞群体的进行性损伤，最终导致残疾或死亡。由于对其发病机制的了解有限，这些疾病仍然缺乏有效的治疗方法，这些发病机制涉及多个细胞和分子途径。免疫反应的触发是神经退行性疾病的共同特征。一个关键的挑战是神经炎症、神经退行性变和免疫反应之间错综复杂的相互作用，这些作用尚未完全描述。近年来，环鸟苷酸-腺苷酸合酶（cGAS）-干扰素基因刺激物（STING）途径作为一种细胞内 DNA 感应的关键免疫反应逐渐受到关注。然而，该途径在免疫细胞、神经胶质细胞和神经元细胞等细胞类型中的具体作用及其对 ND 发病机制的贡献仍未完全阐明。在这篇综述中，我们系统地探讨了 cGAS-STING 信号通路如何在 NDs 背景下将各种细胞类型与相关的细胞效应途径联系起来，为多方面的治疗方向提供信息。我们强调了 cGAS-STING 通路中条件依赖性细胞异质性的发现，这对于理解不同的细胞反应和潜在的治疗靶点至关重要。此外，我们还综述了 cGAS-STING 激活在帕金森病、共济失调毛细血管扩张症和肌萎缩侧索硬化症中的致病作用。我们重点研究了 cGAS-STING 通路在阿尔茨海默病、亨廷顿病和多发性硬化症中的复杂双向作用，揭示了其在疾病进展中的双刃剑性质。本综述的目的是阐明 cGAS-STING 通路在 ND 发病机制中的关键作用，并为促进新的治疗策略的发展提供新的见解。
