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We investigated glucosylceramide (GlcCer) accumulation in human, mouse, and cellular PD models. Lipidomic analyses revealed elevated plasma GlcCer, especially GlcCer24:1, and a shift in phosphatidylcholine (PC) species in PD patients. PD patient skin fibroblasts accumulated more GlcCer under lysosomal stress. GlcCer and sulfatides (SHexCer) were increased in Pink1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    SNCA\n                    <jats:sup>A53T<\/jats:sup>\n                    PD mouse brains, and HT22 neurons exposed to preformed \u03b1Syn fibrils accumulated GlcCer and ceramides. GlcCer24:1 enhanced fibril toxicity, but had no direct or indirect effect on G-protein coupled receptors. RNAseq of GlcCer24:1-treated dorsal root ganglion neurons showed upregulation of glycolipid response genes, similar to pathogen-related signaling. These data indicate extracellular GlcCer is elevated in PD and triggers innate immune responses in sensory neurons.\n                  <\/jats:p>","DOI":"10.1038\/s41531-025-01114-9","type":"journal-article","created":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T04:20:25Z","timestamp":1756527625000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Elevated hexosylceramides in Parkinson\u2019s disease cause gene upregulations in neurons mimicking responses to pathogens"],"prefix":"10.1038","volume":"11","author":[{"given":"Luisa","family":"Franck","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Hahnefeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Valek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Klatt-Schreiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annett","family":"Wilken-Schmitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad Wessam","family":"Alnouri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Trautmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc-Philipp","family":"Weyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Gurke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Offermanns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerd","family":"Geisslinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irmgard","family":"Tegeder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,30]]},"reference":[{"key":"1114_CR1","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1002\/mds.26421","volume":"31","author":"H McCann","year":"2016","unstructured":"McCann, H., Cartwright, H. & Halliday, G. 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