Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Sede Building, 3rd Floor, Barrio de Sarriena s/n, 48940 Leioa, Spain.
Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, UPV/EHU, Barrio de Sarriena s/n, 48940 Leioa, Spain.
Cells. 2023 Jul 17;12(14):1876. doi: 10.3390/cells12141876.
Protein O-GlcNAcylation has been associated with neurodegenerative diseases such as Alzheimer's disease (AD). The O-GlcNAcylation of the Amyloid Precursor Protein (APP) regulates both the trafficking and the processing of the APP through the amyloidogenic pathway, resulting in the release and aggregation of the Aβ peptide. Microglia clears Aβ aggregates and dead cells to maintain brain homeostasis. Here, using LC-MS/MS, we revealed that the Aβ oligomers modify the microglia O-GlcNAcome. We identified 55 proteins, focusing our research on Galectin-1 protein since it is a very versatile protein from a functional point of view. Combining biochemical with genetic approaches, we demonstrated that Aβ oligomers specifically target Galectin-1 O-GlcNAcylation via OGT. In addition to this, the Gal-1-O-GlcNAcylated form, in turn, controls human microglia migration. Given the importance of microglia migration in the progression of AD, this study reports the relationship between the Aβ oligomers and Serine 8-O-GlcNAcylation of Galectin-1 to drive microglial migration.
蛋白质 O-连接的 N-乙酰己糖胺基化与神经退行性疾病有关，如阿尔茨海默病（AD）。淀粉样前体蛋白（APP）的 O-GlcNAcylation 通过淀粉样途径调节 APP 的运输和加工，导致 Aβ肽的释放和聚集。小胶质细胞清除 Aβ 聚集物和死亡细胞以维持大脑内环境平衡。在这里，我们使用 LC-MS/MS 揭示了 Aβ 低聚物修饰小胶质细胞 O-GlcNAcome。我们鉴定了 55 种蛋白质，重点研究半乳糖凝集素-1 蛋白，因为从功能角度来看，它是一种非常多功能的蛋白质。结合生化和遗传方法，我们证明 Aβ 低聚物通过 OGT 特异性靶向 Galectin-1 O-GlcNAcylation。除此之外，Gal-1-O-GlcNAcylated 形式反过来控制人小胶质细胞迁移。鉴于小胶质细胞迁移在 AD 进展中的重要性，本研究报告了 Aβ 低聚物与半乳糖凝集素-1 的丝氨酸 8-O-GlcNAcylation 之间的关系，以驱动小胶质细胞迁移。
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