The STING pathway drives noninflammatory neurodegeneration in NGLY1 deficiency

作者：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 J. Lee, Tadashi Suzuki, Nan Yan · 发表于：The Journal of Experimental Medicine · 年份：2025 · DOI：10.1084/jem.20242296 · 被引用次数：8 · 研究领域：interferon and immune responses、RNA modifications and cancer、RNA regulation and disease

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.