The role of Galectin-3 in α-synuclein-induced microglial activation
Background: Parkinson ’ s disease (PD) is the most prevalent neurodegenerative motor disorder. The neuropathology is characterized by intraneuronal protein aggregates of α -synuclein and progressive degeneration of dopaminergic neurons within the substantia nigra. Previous studies have shown that ex...
| Autores: | , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2014 |
| País: | España |
| Institución: | Universidad de Sevilla (US) |
| Repositorio: | idUS. Depósito de Investigación de la Universidad de Sevilla |
| OAI Identifier: | oai:idus.us.es:11441/41539 |
| Acceso en línea: | http://hdl.handle.net/11441/41539 https://doi.org/10.1186/s40478-014-0156-0 |
| Access Level: | acceso abierto |
| Palabra clave: | Microglia Galectin-3 Neuroinflammation α -synuclein Parkinson’s disease |
| Sumario: | Background: Parkinson ’ s disease (PD) is the most prevalent neurodegenerative motor disorder. The neuropathology is characterized by intraneuronal protein aggregates of α -synuclein and progressive degeneration of dopaminergic neurons within the substantia nigra. Previous studies have shown that extracellular α -synuclein aggregates can activate microglial cells, induce inflammation and contribute to the neurodegenerative process in PD. However, the signaling pathways involved in α -synuclein-mediated microglia activation are poorly understood. Galectin-3 is a member of a carbohydrate-binding protein family involved in cell activation and inflammation. Therefore, we investigated whether galectin-3 is involved in the microglia activation triggered by α -synuclein. Results: We cultured microglial (BV2) cells and induced cell activation by addition of exogenous α -synuclein monomers or aggregates to the cell culture medium. This treatment induced a significant increase in the levels of proinflammatory mediators including the inducible Nitric Oxide Synthase (iNOS), interleukin 1 Beta (IL-1 β ) and Interleukin-12 (IL-12). We then reduced the levels of galectin-3 expression using siRNA or pharmacologically targeting galectin-3 activity using bis-(3-deoxy-3-(3-fluorophenyl-1 H -1,2,3-triazol-1-yl)- β -D-galactopyranosyl)-sulfane. Both approaches led to a significant reduction in the observed inflammatory response induced by α -synuclein. We confirmed these findings using primary microglial cells obtained from wild-type and galectin-3 null mutant mice. Finally, we performed injections of α -synuclein in the olfactory bulb of wild type mice and observed that some of the α -synuclein was taken up by activated microglia that were immunopositive for galectin-3. Conclusions: We show that α -synuclein aggregates induce microglial activation and demonstrate for the first time that galectin-3 plays a significant role in microglia activation induced by α -synuclein. These results suggest that genetic down-regulation or pharmacological inhibition of galectin-3 might constitute a novel therapeutic target in PD and other synucleinopathies |
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