ArticleThe Journal of experimental medicine2025
The STING pathway drives noninflammatory neurodegeneration in NGLY1 deficiency.
Article in The Journal of experimental medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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Who cites it
6 citing papers in PubMed.
- Impacts of N-glycanase1 (NGLY1) Down Regulation on the Function of Mitochondria.Journal of cellular biochemistry · 2026Article
- Natural history of NGLY1 deficiency: motor function & clinical features.Human molecular genetics · 2026Article
- Mechanistic insights and therapeutic potential of targeting the cGAS-STING pathway in neurodegenerative diseases.Journal of neuroinflammation · 2026Review
- PARP7 protects the lung epithelial barrier from diverse environmental threats.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Progressive neurodegeneration, motor decline, and premature mortality in aging Ngly1 deficient rats.Orphanet journal of rare diseases · 2026Article
- NGLY1 as an Emerging Critical Modulator for Neurodevelopment and Pathogenesis in the Brain.International journal of molecular sciences · 2025Review
Corrections and comments
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Authors and funding
16 authors.
Funding
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.
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Registered trials
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