Blumenreich Shani, Nehushtan Tamar, Kupervaser Meital, Shalit Tali, Gabashvili Alexandra, Joseph Tammar, Milenkovic Ivan, Hardy John, Futerman Anthony H
Department of Biomolecular Sciences, Rehovot, 76100, Israel.
Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, 76100, Israel.
NPJ Parkinsons Dis. 2024 Feb 8;10(1):33. doi: 10.1038/s41531-024-00645-x.
Despite being the second most common neurodegenerative disorder, little is known about Parkinson's disease (PD) pathogenesis. A number of genetic factors predispose towards PD, among them mutations in GBA1, which encodes the lysosomal enzyme acid-β-glucosidase. We now perform non-targeted, mass spectrometry based quantitative proteomics on five brain regions from PD patients with a GBA1 mutation (PD-GBA) and compare to age- and sex-matched idiopathic PD patients (IPD) and controls. Two proteins were differentially-expressed in all five brain regions whereas significant differences were detected between the brain regions, with changes consistent with loss of dopaminergic signaling in the substantia nigra, and activation of a number of pathways in the cingulate gyrus, including ceramide synthesis. Mitochondrial oxidative phosphorylation was inactivated in PD samples in most brain regions and to a larger extent in PD-GBA. This study provides a comprehensive large-scale proteomics dataset for the study of PD-GBA.
尽管帕金森病(PD)是第二常见的神经退行性疾病,但其发病机制仍知之甚少。许多遗传因素易导致PD,其中包括编码溶酶体酶酸性β-葡萄糖苷酶的GBA1基因突变。我们现在对携带GBA1突变的PD患者(PD-GBA)的五个脑区进行非靶向、基于质谱的定量蛋白质组学分析,并与年龄和性别匹配的特发性PD患者(IPD)及对照组进行比较。有两种蛋白质在所有五个脑区中均存在差异表达,而在不同脑区之间也检测到了显著差异,这些变化与黑质中多巴胺能信号的丧失以及扣带回中多种信号通路的激活一致,包括神经酰胺合成。在大多数脑区的PD样本中,线粒体氧化磷酸化被抑制,在PD-GBA中抑制程度更大。本研究为PD-GBA的研究提供了一个全面的大规模蛋白质组学数据集。