NPJ Parkinson's disease · 2025
Elevated hexosylceramides in Parkinson's disease cause gene upregulations in neurons mimicking responses to pathogens.
СтатьяНазвание и аннотация: Перевод в очереди
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Franck Luisa, Hahnefeld Lisa, Valek Lucie, Klatt-Schreiner Katharina, Wilken-Schmitz Annett, Alnouri Mohamad Wessam, Trautmann Sandra, Weyer Marc-Philipp, Thomas Dominique, Gurke Robert, Offermanns Stefan, Geisslinger Gerd, Tegeder Irmgard
Аннотация
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.