A number of genetic risk factors have been identified over the past decade for Parkinson’s Disease (PD), with variants in GBA prominent among them. GBA encodes the lysosomal enzyme that degrades the glycosphingolipid, glucosylceramide (GlcCer), with the activity of this enzyme defective in Gaucher disease. Based on the ill-defined relationship between glycosphingolipid metabolism and PD, we now analyze levels of various lipids by liquid chromatography/electrospray ionization-tandem mass spectrometry in four brain regions from age- and sex-matched patient samples, including idiopathic PD, PD patients with a GBA mutation and compare both to control brains (n = 21 for each group) obtained from individuals who died from a cause unrelated to PD. Of all the glycerolipids, sterols, and (glyco)sphingolipids (251 lipids in total), the only lipid class which showed significant differences were the gangliosides (sialic acid-containing complex glycosphingolipids), which were elevated in 3 of the 4 PD-GBA brain regions. There was no clear correlation between levels of individual gangliosides and the genetic variant in Gaucher disease [9 samples of severe (neuronopathic), 4 samples of mild (non-neuronopathic) GBA variants, and 8 samples with low pathogenicity variants which have a higher risk for development of PD]. Most brain regions, i.e. occipital cortex, cingulate gyrus, and striatum, did not show a statistically significant elevation of GlcCer in PD-GBA. Only one region, the middle temporal gyrus, showed a small, but significant elevation in GlcCer concentration in PD-GBA. We conclude that changes in ganglioside, but not in GlcCer levels, may contribute to the association between PD and GBA mutations.

在过去的十年中，已经确定了帕金森氏病 (PD) 的许多遗传风险因素，其中突出的是GBA变异。GBA编码降解糖鞘脂、葡萄糖神经酰胺 (GlcCer) 的溶酶体酶，这种酶的活性在戈谢病中存在缺陷。基于鞘糖脂代谢与 PD 之间不明确的关系，我们现在通过液相色谱/电喷雾电离-串联质谱法分析来自年龄和性别匹配的患者样本的四个脑区的各种脂质水平，包括特发性 PD、PD 患者具有GBA突变并将两者与对照大脑进行比较（n = 每组 21 个）从死于与 PD 无关的原因的个体获得。在所有甘油脂、甾醇和（糖）鞘脂（总共 251 种脂质）中，唯一显示出显着差异的脂质类别是神经节苷脂（含唾液酸的复合糖鞘脂），其在 4 个 PD-GBA 中的 3 个中升高大脑区域。个体神经节苷脂的水平与戈谢病的遗传变异之间没有明显的相关性 [9 个重度（神经元病）样本，4 个轻度（非神经元病）GBA样本变体，以及 8 个具有低致病性变体的样本，这些变体具有更高的 PD 发展风险]。大多数大脑区域，即枕叶皮层、扣带回和纹状体，在 PD-GBA 中没有显示出具有统计学意义的 GlcCer 升高。只有一个区域，即颞中回，在 PD-GBA 中显示出小幅但显着的 GlcCer 浓度升高。我们得出结论，神经节苷脂的变化，而不是 GlcCer 水平的变化，可能有助于 PD 和GBA突变之间的关联。