The role of Galectin-3 in α-synuclein-induced microglial activation.

Abstract

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-1β) 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-1H-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.

• Authors: Antonio Boza-Serrano, Juan F Reyes, Nolwen L Rey, Hakon Leffler, Luc Bousset, Ulf Nilsson, Patrik Brundin, Jose Luis Venero, Miguel Angel Burguillos, Tomas Deierborg
• Journal: Acta neuropathologica communications (Acta Neuropathol Commun) Vol. 2 Pg. 156 (Nov 12 2014) ISSN: 2051-5960 [Electronic] England
• PMID: 25387690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Galectin 3
• IL1B protein, mouse
• Interleukin-1beta
• Lgals3 protein, mouse
• RNA, Small Interfering
• Recombinant Proteins
• Snca protein, mouse
• alpha-Synuclein
• Interleukin-12
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse

Topics

• Animals
• Cell Line
• Cell Survival (drug effects, physiology)
• Cells, Cultured
• Female
• Galectin 3 (antagonists & inhibitors, genetics, metabolism)
• Interleukin-12 (metabolism)
• Interleukin-1beta (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microglia (drug effects, physiology)
• Neuroimmunomodulation (physiology)
• Nitric Oxide Synthase Type II (metabolism)
• Olfactory Bulb (immunology)
• Phagocytosis (drug effects, physiology)
• RNA, Small Interfering
• Recombinant Proteins (administration & dosage)
• alpha-Synuclein (administration & dosage, metabolism)