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Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI
npj Parkinson's Disease ( IF 6.7 ) Pub Date : 2021-11-22 , DOI: 10.1038/s41531-021-00241-3
Young Eun Huh 1, 2, 3, 4 , Hyejung Park 5 , Ming Sum Ruby Chiang 6 , Idil Tuncali 1, 2, 3 , Ganqiang Liu 1, 2, 3, 7 , Joseph J Locascio 1, 2, 3, 8 , Julia Shirvan 1, 8 , Samantha J Hutten 9 , Melissa S Rotunno 6 , Catherine Viel 6 , Lamya S Shihabuddin 6 , Bing Wang 5 , Sergio Pablo Sardi 6 , Clemens R Scherzer 1, 2, 3, 8
Affiliation  

Protein-coding variants in the GBA gene modulate susceptibility and progression in ~10% of patients with Parkinson’s disease (PD). GBA encodes the β-glucocerebrosidase enzyme that hydrolyzes glucosylceramide. We hypothesized that GBA mutations will lead to glucosylceramide accumulation in cerebrospinal fluid (CSF). Glucosylceramide, ceramide, sphingomyelin, and lactosylceramide levels were measured by liquid chromatography-tandem mass spectrometry in CSF of 411 participants from the Parkinson’s Progression Markers Initiative (PPMI) cohort, including early stage, de novo PD patients with abnormal dopamine transporter neuroimaging and healthy controls. Forty-four PD patients carried protein-coding GBA variants (GBA-PD) and 227 carried wild-type alleles (idiopathic PD). The glucosylceramide fraction was increased (P = 0.0001), and the sphingomyelin fraction (a downstream metabolite) was reduced (P = 0.0001) in CSF of GBA-PD patients compared to healthy controls. The ceramide fraction was unchanged, and lactosylceramide was below detection limits. We then used the ratio of glucosylceramide to sphingomyelin (the GlcCer/SM ratio) to explore whether these two sphingolipid fractions altered in GBA-PD were useful for stratifying idiopathic PD patients. Idiopathic PD patients in the top quartile of GlcCer/SM ratios at baseline showed a more rapid decline in Montreal Cognitive Assessment scores during longitudinal follow-up compared to those in the lowest quartile with a P-value of 0.036. The GlcCer/SM ratio was negatively associated with α-synuclein levels in CSF of PD patients. This study highlights glucosylceramide as a pathway biomarker for GBA-PD patients and the GlcCer/SM ratio as a potential stratification tool for clinical trials of idiopathic PD patients. Our sphingolipids data together with the clinical, imaging, omics, and genetic characterization of PPMI will contribute a useful resource for multi-modal biomarkers development.



中文翻译:

参加 PPMI 的 GBA 相关和特发性帕金森病患者脑脊液中的葡萄糖神经酰胺

GBA基因中的蛋白质编码变体调节约 10% 的帕金森病 (PD) 患者的易感性和进展。GBA编码水解葡糖神经酰胺的 β-葡糖脑苷脂酶。我们假设GBA突变会导致脑脊液 (CSF) 中葡萄糖神经酰胺的积累。通过液相色谱-串联质谱法测量来自帕金森病进展标志物倡议 (PPMI) 队列的 411 名参与者的脑脊液中的葡萄糖神经酰胺、神经酰胺、鞘磷脂和乳糖神经酰胺水平,包括多巴胺转运蛋白神经成像异常的早期 PD 患者和健康对照. 44 名 PD 患者携带蛋白质编码的GBA变异(GBA-PD)和 227 个携带野生型等位基因(特发性 PD)。与健康对照相比 ,GBA- PD 患者脑脊液中的葡萄糖神经酰胺分数增加(P  = 0.0001),鞘磷脂分数(下游代谢物)减少(P = 0.0001)。神经酰胺部分没有变化,乳糖神经酰胺低于检测限。然后我们使用葡萄糖神经酰胺与鞘磷脂的比率(GlcCer/SM 比率)来探索这两种鞘脂组分在GBA 中是否发生了变化-PD 可用于对特发性 PD 患者进行分层。与P值为 0.036的最低四分位数的患者相比,基线时 GlcCer/SM 比率最高四分位数的特发性 PD 患者在纵向随访期间的蒙特利尔认知评估评分下降更快。GlcCer/SM 比值与 PD 患者脑脊液中的α-突触核蛋白水平呈负相关。这项研究强调了葡萄糖神经酰胺作为GBA -PD 患者的通路生物标志物和 GlcCer/SM 比率作为特发性 PD 患者临床试验的潜在分层工具。我们的鞘脂数据以及 PPMI 的临床、成像、组学和遗传特征将为多模式生物标志物的开发提供有用的资源。

更新日期:2021-11-22
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