Luisa Franck, Lisa Hahnefeld, Lucie Valek, Katharina Klatt-Schreiner, Annett Wilken-Schmitz, Mohamad Wessam Alnouri, Sandra Trautmann, Marc-Philipp Weyer, Dominique Thomas, Robert Gurke, Stefan Offermanns, Gerd Geisslinger, Irmgard Tegeder
{"title":"帕金森病中升高的己糖神经酰胺引起神经元对病原体反应的基因上调","authors":"Luisa Franck, Lisa Hahnefeld, Lucie Valek, Katharina Klatt-Schreiner, Annett Wilken-Schmitz, Mohamad Wessam Alnouri, Sandra Trautmann, Marc-Philipp Weyer, Dominique Thomas, Robert Gurke, Stefan Offermanns, Gerd Geisslinger, Irmgard Tegeder","doi":"10.1038/s41531-025-01114-9","DOIUrl":null,"url":null,"abstract":"<p>Parkinson’s Disease (PD) is driven by pathological aggregates of alpha-synuclein (αSyn), whose formation is facilitated by impaired glycosphingolipid metabolism via acidic glucocerebrosidase (GCase). 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<sup>−/−</sup>SNCA<sup>A53T</sup> PD mouse brains, and HT22 neurons exposed to preformed αSyn 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.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"93 1","pages":""},"PeriodicalIF":8.2000,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Elevated hexosylceramides in Parkinson’s disease cause gene upregulations in neurons mimicking responses to pathogens\",\"authors\":\"Luisa Franck, Lisa Hahnefeld, Lucie Valek, Katharina Klatt-Schreiner, Annett Wilken-Schmitz, Mohamad Wessam Alnouri, Sandra Trautmann, Marc-Philipp Weyer, Dominique Thomas, Robert Gurke, Stefan Offermanns, Gerd Geisslinger, Irmgard Tegeder\",\"doi\":\"10.1038/s41531-025-01114-9\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Parkinson’s Disease (PD) is driven by pathological aggregates of alpha-synuclein (αSyn), whose formation is facilitated by impaired glycosphingolipid metabolism via acidic glucocerebrosidase (GCase). 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<sup>−/−</sup>SNCA<sup>A53T</sup> PD mouse brains, and HT22 neurons exposed to preformed αSyn 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.</p>\",\"PeriodicalId\":19706,\"journal\":{\"name\":\"NPJ Parkinson's Disease\",\"volume\":\"93 1\",\"pages\":\"\"},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2025-08-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"NPJ Parkinson's Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41531-025-01114-9\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"NPJ Parkinson's Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41531-025-01114-9","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Elevated hexosylceramides in Parkinson’s disease cause gene upregulations in neurons mimicking responses to pathogens
Parkinson’s Disease (PD) is driven by pathological aggregates of alpha-synuclein (αSyn), whose formation is facilitated by impaired glycosphingolipid metabolism via acidic glucocerebrosidase (GCase). 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−/−SNCAA53T PD mouse brains, and HT22 neurons exposed to preformed αSyn 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.
期刊介绍：
npj Parkinson's Disease is a comprehensive open access journal that covers a wide range of research areas related to Parkinson's disease. It publishes original studies in basic science, translational research, and clinical investigations. The journal is dedicated to advancing our understanding of Parkinson's disease by exploring various aspects such as anatomy, etiology, genetics, cellular and molecular physiology, neurophysiology, epidemiology, and therapeutic development. By providing free and immediate access to the scientific and Parkinson's disease community, npj Parkinson's Disease promotes collaboration and knowledge sharing among researchers and healthcare professionals.
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