Amyloid β Oligomers Induce Galectin-1 O-GlcNAcylation Leading to Microglia Migration

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2023 Jul 29

PMID 37508540

Authors

Alazne Arrazola Sastre

Miriam Luque Montoro

Francisco Llavero

Jose L Zugaza

Affiliations

Soon will be listed here.

Abstract

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.

References

Mertins P, Mani D, Ruggles K, Gillette M, Clauser K, Wang P . Proteogenomics connects somatic mutations to signalling in breast cancer. Nature. 2016; 534(7605):55-62. PMC: 5102256. DOI: 10.1038/nature18003. View

Walsh D, Thulin E, Minogue A, Gustavsson N, Pang E, Teplow D . A facile method for expression and purification of the Alzheimer's disease-associated amyloid beta-peptide. FEBS J. 2009; 276(5):1266-81. PMC: 2702495. DOI: 10.1111/j.1742-4658.2008.06862.x. View

Wenzel D, Olivier-Van Stichelen S . The O-GlcNAc cycling in neurodevelopment and associated diseases. Biochem Soc Trans. 2022; 50(6):1693-1702. PMC: 10462390. DOI: 10.1042/BST20220539. View

Nio-Kobayashi J, Itabashi T . Galectins and Their Ligand Glycoconjugates in the Central Nervous System Under Physiological and Pathological Conditions. Front Neuroanat. 2021; 15:767330. PMC: 8554236. DOI: 10.3389/fnana.2021.767330. View

Camby I, Mercier M, Lefranc F, Kiss R . Galectin-1: a small protein with major functions. Glycobiology. 2006; 16(11):137R-157R. DOI: 10.1093/glycob/cwl025. View

Starossom S, Mascanfroni I, Imitola J, Cao L, Raddassi K, Hernandez S . Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration. Immunity. 2012; 37(2):249-63. PMC: 3428471. DOI: 10.1016/j.immuni.2012.05.023. View

Chun Y, Kwon O, Chung S . O-GlcNAcylation of amyloid-β precursor protein at threonine 576 residue regulates trafficking and processing. Biochem Biophys Res Commun. 2017; 490(2):486-491. DOI: 10.1016/j.bbrc.2017.06.067. View

Mertins P, Yang F, Liu T, Mani D, Petyuk V, Gillette M . Ischemia in tumors induces early and sustained phosphorylation changes in stress kinase pathways but does not affect global protein levels. Mol Cell Proteomics. 2014; 13(7):1690-704. PMC: 4083109. DOI: 10.1074/mcp.M113.036392. View

Hickman S, Allison E, El Khoury J . Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci. 2008; 28(33):8354-60. PMC: 2597474. DOI: 10.1523/JNEUROSCI.0616-08.2008. View

10.

Park J, Ha H, Chung E, Baek S, Cho Y, Kim H . -GlcNAcylation ameliorates the pathological manifestations of Alzheimer's disease by inhibiting necroptosis. Sci Adv. 2021; 7(3). PMC: 7806231. DOI: 10.1126/sciadv.abd3207. View

11.

Slawson C, Hart G . O-GlcNAc signalling: implications for cancer cell biology. Nat Rev Cancer. 2011; 11(9):678-84. PMC: 3291174. DOI: 10.1038/nrc3114. View

12.

Xu F, Xu Y, Zhu L, Rao P, Wen J, Sang Y . Fasudil inhibits LPS-induced migration of retinal microglial cells via regulating p38-MAPK signaling pathway. Mol Vis. 2016; 22:836-46. PMC: 4951004. View

13.

Gong C, Iqbal K . Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. Curr Med Chem. 2008; 15(23):2321-8. PMC: 2656563. DOI: 10.2174/092986708785909111. View

14.

Ortiz-Meoz R, Jiang J, Lazarus M, Orman M, Janetzko J, Fan C . A small molecule that inhibits OGT activity in cells. ACS Chem Biol. 2015; 10(6):1392-7. PMC: 4475500. DOI: 10.1021/acschembio.5b00004. View

15.

Blazevits O, Mideksa Y, Solman M, Ligabue A, Ariotti N, Nakhaeizadeh H . Galectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering. Sci Rep. 2016; 6:24165. PMC: 4834570. DOI: 10.1038/srep24165. View

16.

Cedeno-Laurent F, Dimitroff C . Galectin-1 research in T cell immunity: past, present and future. Clin Immunol. 2011; 142(2):107-16. PMC: 3266984. DOI: 10.1016/j.clim.2011.09.011. View

17.

Elola M, Ferragut F, Mendez-Huergo S, Croci D, Bracalente C, Rabinovich G . Galectins: Multitask signaling molecules linking fibroblast, endothelial and immune cell programs in the tumor microenvironment. Cell Immunol. 2018; 333:34-45. DOI: 10.1016/j.cellimm.2018.03.008. View

18.

Liu F, Iqbal K, Grundke-Iqbal I, Hart G, Gong C . O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004; 101(29):10804-9. PMC: 490015. DOI: 10.1073/pnas.0400348101. View

19.

Yuzwa S, Vocadlo D . O-GlcNAc and neurodegeneration: biochemical mechanisms and potential roles in Alzheimer's disease and beyond. Chem Soc Rev. 2014; 43(19):6839-58. DOI: 10.1039/c4cs00038b. View

20.

Pravata V, Omelkova M, Stavridis M, Desbiens C, Stephen H, Lefeber D . An intellectual disability syndrome with single-nucleotide variants in O-GlcNAc transferase. Eur J Hum Genet. 2020; 28(6):706-714. PMC: 7253464. DOI: 10.1038/s41431-020-0589-9. View