The STING pathway drives noninflammatory neurodegeneration in NGLY1 deficiency.

IF 12.6 1区 医学 Q1 IMMUNOLOGY
Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-07-11 DOI:10.1084/jem.20242296
Kun Yang, Gustavo Torres-Ramirez, Nicole Dobbs, Jie Han, Makoto Asahina, Reiko Fujinawa, Kun Song, Yun Liu, Weichun Lin, Angelica Oviedo, Chuo Chen, Lei Zhu, William F Mueller, Kevin Lee, Tadashi Suzuki, Nan Yan
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引用次数: 0

Abstract

The STING pathway is increasingly recognized as a key regulator of neuroinflammation in neurodegenerative disease, but its role in noninflammatory conditions remains unclear. We generated a postnatal inducible whole-body Ngly1 knockout mouse (iNgly1-/-) to model NGLY1 deficiency, an early-onset neurodegenerative disorder. iNgly1-/- mice exhibit progressive motor deficits, Purkinje cell loss, and shortened lifespan without evidence of gliosis or immune activation. Cell type-specific deletion of Ngly1 in Purkinje cells or microglia failed to induce disease, suggesting multiple cell-intrinsic and cell-extrinsic signals are required. Genetic ablation of Sting1 in iNgly1-/- mice rescues Purkinje cell loss, improves motor function, and extends lifespan. Single-nucleus RNA sequencing reveals proteostasis disruption in Purkinje cells, altered cerebellar granule cell subpopulations, and STING-dependent suppression of cholesterol biosynthesis in glia. Pharmacological inhibition of STING with an orally bioactive antagonist, VS-X4, significantly mitigates neuropathology and motor disease. These findings identify STING as a key mediator of neuropathology in NGLY1 deficiency and implicate a role of STING in noninflammatory neurological disease.

STING通路驱动NGLY1缺乏症的非炎症性神经变性。
越来越多的人认为STING通路是神经退行性疾病中神经炎症的关键调节因子,但其在非炎症性疾病中的作用尚不清楚。我们制造了一只出生后可诱导的全身Ngly1敲除小鼠(iNgly1-/-)来模拟Ngly1缺乏症(一种早发性神经退行性疾病)。iNgly1-/-小鼠表现出进行性运动障碍,浦肯野细胞丢失,寿命缩短,无胶质细胞增生或免疫激活的证据。浦肯野细胞或小胶质细胞中Ngly1的细胞类型特异性缺失未能诱导疾病,这表明需要多种细胞内在和细胞外在信号。基因消融iNgly1-/-小鼠的Sting1可挽救浦肯野细胞损失,改善运动功能,延长寿命。单核RNA测序揭示了浦肯野细胞的蛋白质稳态破坏,小脑颗粒细胞亚群的改变,以及胶质细胞中胆固醇生物合成的sting依赖性抑制。口服生物活性拮抗剂VS-X4对STING的药理抑制可显著减轻神经病理和运动疾病。这些发现确定了STING是NGLY1缺乏神经病理学的关键介质,并暗示了STING在非炎症性神经疾病中的作用。
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来源期刊
CiteScore
26.60
自引率
1.30%
发文量
189
审稿时长
3-8 weeks
期刊介绍: Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field. Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions. Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.
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