Background:As mutations in glucocerebrosidase 1 (GBA1) are a major risk factor for Parkinson’s disease (PD), decreased GBA1 activity might play an important role in the pathogenesis of the disease. However, there are currently no reports on glucosylceramide levels in the cerebrospinal fluid (CSF) in PD. Objective:We investigated whether glucosylceramide accumulation and abnormal immune status in the brain are associated with PD. Methods:We measured glucosylceramide by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) as well as levels of the active fragment of complement C5, C5a, in the CSF of 33 PD, 15 amyotrophic lateral sclerosis (ALS) and 22 neurologically normal control (NNC) subjects. Serum C5a levels in all PD and ALS cases and in a limited number of NNC subjects (n = 8) were also measured. Results:C5a levels in CSF were significantly downregulated in PD compared with NNC. Moreover, CSF C5a/serum C5a ratio showed pronounced perturbations in PD and ALS patients. LC-ESI-MS/MS revealed a statistically significant accumulation of a specific subspecies of glucosylceramide (d18 : 1/C23 : 0 acyl chain fatty acid) in ALS, but not in PD. Interestingly, CSF glucosylceramide (d18 : 1/C23 : 0) exhibited a significant correlation with CSF C5a levels in PD, but not ALS. No correlation was observed between C5a levels or glucosylceramide subspecies content and disease duration, levodopa equivalent daily dose or Hoehn & Yahr staging in PD. Conclusion:Our findings demonstrate complement dysregulation without glucosylceramide accumulation in PD CSF. Furthermore, we found an association between a specific glucosylceramide subspecies and immune status in PD.

中文翻译：

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帕金森病的脑脊液分布：没有葡萄糖神经酰胺的积累，但活性补体 C5 片段的显着下调

背景：由于葡萄糖脑苷脂酶 1 (GBA1) 的突变是帕金森病 (PD) 的主要危险因素，因此 GBA1 活性降低可能在该病的发病机制中起重要作用。然而，目前没有关于 PD 脑脊液 (CSF) 中葡萄糖神经酰胺水平的报道。目的：我们研究了大脑中葡萄糖神经酰胺的积累和异常的免疫状态是否与 PD 相关。方法：我们通过液相色谱-电喷雾电离-串联质谱（LC-ESI-MS/MS）测定了 33 名 PD、15 名肌萎缩侧索硬化患者脑脊液中补体 C5、C5a 活性片段的水平。 ALS) 和 22 名神经正常对照 (NNC) 受试者。还测量了所有 PD 和 ALS 病例以及有限数量的 NNC 受试者 (n = 8) 中的血清 C5a 水平。结果：与 NNC 相比，PD 患者脑脊液中的 C5a 水平显着下调。此外，脑脊液 C5a/血清 C5a 比率在 PD 和 ALS 患者中显示出明显的扰动。LC-ESI-MS/MS 揭示了特定亚种葡萄糖神经酰胺（d18:1/C23:0 酰基链脂肪酸）在 ALS 中的显着积累，但在 PD 中没有。有趣的是，脑脊液葡糖神经酰胺（d18：1/C23：0）与 PD 中的脑脊液 C5a 水平显着相关，但与 ALS 无关。C5a 水平或葡萄糖神经酰胺亚种含量与疾病持续时间、左旋多巴等效日剂量或 PD 的 Hoehn & Yahr 分期之间没有观察到相关性。结论：我们的研究结果表明补体失调，而 PD CSF 中没有葡萄糖神经酰胺积累。此外，我们发现特定葡萄糖神经酰胺亚种与 PD 免疫状态之间存在关联。