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We found that GC accumulation within microglia induced by pharmacological inhibition of GCase triggered STING-dependent inflammation, which contributed to neuronal loss both in vitro and in vivo. GC accumulation in microglia induced mitochondrial DNA (mtDNA) leakage to the cytosol to trigger STING-dependent inflammation. Rapamycin, a compound that promotes lysosomal activity, improved mitochondrial function, thereby decreasing STING signaling. Furthermore, lysosomal damage caused by GC accumulation led to defects in the degradation of activated STING, further exacerbating inflammation mediated by microglia. Thus, limiting STING activity may be a strategy to suppress neuroinflammation caused by GCase deficiency.<\/jats:p>","DOI":"10.1126\/scisignal.adk8249","type":"journal-article","created":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T17:58:40Z","timestamp":1711475920000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":46,"title":["Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8346-5783","authenticated-orcid":true,"given":"Rui","family":"Wang","sequence":"first","affiliation":[{"name":"School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, Jiangsu 210096, China."},{"name":"Center of Translational Medicine, First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou, 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