Blumenreich Shani, Nehushtan Tamar, Barav Or B, Saville Jennifer T, Dingjan Tamir, Hardy John, Fuller Maria, Futerman Anthony H
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 7610001, Israel.
Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital and Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia.
NPJ Parkinsons Dis. 2022 Aug 6;8(1):99. doi: 10.1038/s41531-022-00363-2.
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.
在过去十年中，已确定了帕金森病（PD）的一些遗传风险因素，其中GBA基因变异尤为突出。GBA编码一种溶酶体酶，该酶可降解糖鞘脂葡萄糖神经酰胺（GlcCer），在戈谢病中这种酶的活性存在缺陷。基于糖鞘脂代谢与PD之间尚不明确的关系，我们现在通过液相色谱/电喷雾电离串联质谱法分析了年龄和性别匹配的患者样本（包括特发性PD、携带GBA突变的PD患者）四个脑区中各种脂质的水平，并将其与从死于与PD无关原因的个体获得的对照脑样本（每组n = 21）进行比较。在所有甘油脂、固醇和（糖）鞘脂（总共251种脂质）中，唯一显示出显著差异的脂质类别是神经节苷脂（含唾液酸的复合糖鞘脂），在4个PD - GBA脑区中的3个区域升高。个体神经节苷脂水平与戈谢病的基因变异之间没有明显的相关性[9个严重（神经病型）样本、4个轻度（非神经病型）GBA变异样本以及8个具有较高PD发病风险的低致病性变异样本]。大多数脑区，即枕叶皮质、扣带回和纹状体，在PD - GBA中未显示出GlcCer有统计学意义的升高。只有一个区域，即颞中回，在PD - GBA中显示出GlcCer浓度有小幅但显著的升高。我们得出结论，神经节苷脂水平的变化而非GlcCer水平的变化，可能有助于解释PD与GBA突变之间的关联。
