Department of Neurosciences and Mental Health, Neurology, Hospital de Santa Maria- CHLN, Lisbon, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Columbia University Medical Center, Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA.
Parkinsonism Relat Disord. 2017 Nov;44:58-65. doi: 10.1016/j.parkreldis.2017.08.026. Epub 2017 Sep 1.
Mutations in the GBA gene, encoding for the lysosomal enzyme glucocerebrosidase, are associated with Gaucher disease. Alterations in plasma sphingolipids have been reported in Gaucher, and similarly in brain extracts in Lewy body disease. As GBA mutations are prevalent risk factors for Parkinson's disease and overlap of molecular pathways are presumable, here we assessed the lipid profiles in Parkinson's patients with and without GBA mutations.
We sequenced all GBA exons in 415 Parkinson's patients, previously genotyped for LRRK2. 64 patients (29 GBA positive vs. 35 non-GBA-carriers including 18 LRRK2 positive and 17 non-mutated) were analyzed for chitotriosidase activity and for the concentration of 40 lipid classes using HPLC-MS.
29/415 patients (6.9%) carried 8 different GBA mutations associated with Gaucher or Parkinson's, including one novel mutation. Chitotriosidase activity was similar across the genetic groups, while the levels of key lipids were altered in GBA mutation carriers: Monohexosylceramide, Ceramide and Sphingomyelin were elevated; while Phosphatidic acid (PA), Phosphatidylethanolamine (PE), Plasmalogen phosphatidylethanolamine (PEp) and Acyl Phosphatidylglycerol (AcylPG) were decreased.
The results suggest an important role for these lipids in GBA mediated Parkinson's disease and assist in the identification of common pathways between Gaucher and Parkinson's. Ultimately, our findings may lead to the identification of novel biomarkers for individuals at increased risk of developing Parkinson's disease.
编码溶酶体酶葡萄糖脑苷脂酶的 GBA 基因突变与戈谢病有关。戈谢病患者的血浆神经鞘脂发生改变，而路易体病患者的大脑提取物也有类似改变。由于 GBA 突变是帕金森病的常见危险因素，且分子途径可能重叠，因此我们在此评估了携带和不携带 GBA 突变的帕金森病患者的脂质谱。
我们对先前进行过 LRRK2 基因分型的 415 名帕金森病患者进行了 GBA 所有外显子的测序。对 64 名患者（29 名 GBA 阳性 vs. 35 名非 GBA 携带者，包括 18 名 LRRK2 阳性和 17 名未突变）进行了几丁质酶活性分析和使用 HPLC-MS 分析 40 种脂质类别的浓度。
415 名患者中有 29 名（6.9%）携带与戈谢病或帕金森病相关的 8 种不同的 GBA 突变，包括一种新突变。遗传组之间的几丁质酶活性相似，而 GBA 突变携带者的关键脂质水平发生改变：单己糖神经酰胺、神经酰胺和神经鞘磷脂升高；而磷酸丝氨酸（PA）、磷酸乙醇胺（PE）、溶血磷脂酰乙醇胺（PEp）和酰基磷脂酰甘油（AcylPG）降低。
结果表明这些脂质在 GBA 介导的帕金森病中具有重要作用，并有助于确定戈谢病和帕金森病之间的共同途径。最终，我们的发现可能会导致发现具有更高帕金森病风险的个体的新型生物标志物。
