Scholarlink

<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>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Elevated hexosylceramides in Parkinson’s disease cause gene upregulations in neurons mimicking responses to pathogens

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月30日

查看全文
  • 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

摘要

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.