{"doi":"10.1084/jem.20242296","title":"The STING pathway drives noninflammatory neurodegeneration in NGLY1 deficiency","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.","journal":"The Journal of Experimental Medicine","year":2025,"id":517542,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1384532,"name":"Gustavo Torres-Ramirez","orcid":null,"position":1,"is_corresponding":false},{"id":230827,"name":"Nicole Dobbs","orcid":"0000-0003-1944-9740","position":2,"is_corresponding":false},{"id":419768,"name":"Jie Han","orcid":"0000-0001-6994-3371","position":3,"is_corresponding":false},{"id":1383852,"name":"Makoto Asahina","orcid":"0000-0001-5833-7704","position":4,"is_corresponding":false},{"id":1383853,"name":"Reiko Fujinawa","orcid":"0000-0002-9358-3406","position":5,"is_corresponding":false},{"id":1383854,"name":"Kun Song","orcid":"0009-0008-6658-0980","position":6,"is_corresponding":false},{"id":871106,"name":"Yun Liu","orcid":"0000-0003-2063-7132","position":7,"is_corresponding":false},{"id":520584,"name":"Weichun Lin","orcid":"0000-0002-6806-3329","position":8,"is_corresponding":false},{"id":1383855,"name":"Angelica Oviedo","orcid":"0000-0003-2617-5469","position":9,"is_corresponding":false},{"id":7766,"name":"Chuo Chen","orcid":"0000-0002-3118-4901","position":10,"is_corresponding":false},{"id":1383856,"name":"Lei Zhu","orcid":"0000-0002-0898-8602","position":11,"is_corresponding":false},{"id":1065496,"name":"William F. Mueller","orcid":"0000-0001-9134-7648","position":12,"is_corresponding":false},{"id":899584,"name":"Kevin J. Lee","orcid":"0000-0001-9823-0952","position":13,"is_corresponding":false},{"id":351904,"name":"Tadashi Suzuki","orcid":"0000-0003-1030-7631","position":14,"is_corresponding":false},{"id":230829,"name":"Nan Yan","orcid":"0000-0002-0637-3989","position":15,"is_corresponding":false},{"id":230828,"name":"Kun Yang","orcid":"0000-0002-2011-7084","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:48:59.410472Z","pmid":"40644312","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}