論文 - 詳細
| RRC ID | 85332 |
|---|---|
| 著者 | Yang K, Torres-Ramirez G, Dobbs N, Han J, Asahina M, Fujinawa R, Song K, Liu Y, Lin W, Oviedo A, Chen C, Zhu L, Mueller WF, Lee K, Suzuki T, Yan N. |
| タイトル | The STING pathway drives noninflammatory neurodegeneration in NGLY1 deficiency. |
| ジャーナル | J Exp Med |
| 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. |
| 巻・号 | 222(10) |
| 公開日 | 2025-10-6 |
| DOI | 10.1084/jem.20242296 |
| PII | 278113 |
| PMID | 40644312 |
| PMC | PMC12249164 |
| MeSH | Animals Cholesterol / biosynthesis Intracellular Signaling Peptides and Proteins* / deficiency Membrane Proteins* / genetics Membrane Proteins* / metabolism Mice Mice, Inbred C57BL Mice, Knockout Microglia / metabolism Microglia / pathology Neurodegenerative Diseases* / genetics Neurodegenerative Diseases* / metabolism Neurodegenerative Diseases* / pathology Purkinje Cells / metabolism Purkinje Cells / pathology Signal Transduction* |
| IF | 11.743 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 38 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 実験動物マウス | RBRC06293 |