The role of Galectin-3 in α-synuclein-induced microglial activation
Boza-Serrano, Antonio LU ; Reyes, Juan F. LU ; Rey, Nolwen L. LU ; Leffler, Hakon LU ; Bousset, Luc ; Nilsson, Ulf LU ; Brundin, Patrik LU ; Venero, Jose Luis ; Burguillos, Miguel Angel and Deierborg, Tomas LU
(2014)
In Acta Neuropathologica Communications
2.
- 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... (More)
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.
(Less)
- author
- Boza-Serrano, Antonio
LU
; Reyes, Juan F.
LU
; Rey, Nolwen L.
LU
; Leffler, Hakon
LU
; Bousset, Luc
; Nilsson, Ulf
LU
; Brundin, Patrik
LU
; Venero, Jose Luis
; Burguillos, Miguel Angel
and Deierborg, Tomas
LU
- organization
- publishing date
- 2014-01-27
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Galectin-3, Microglia, Neuroinflammation, Parkinson's disease, α-synuclein
- in
- Acta Neuropathologica Communications
- volume
- 2
- article number
- 156
- publisher
- BioMed Central (BMC)
- external identifiers
-
- pmid:25387690
- scopus:84964697525
- ISSN
- 2051-5960
- DOI
- 10.1186/s40478-014-0156-0
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2014 Boza-Serrano et al.; licensee BioMed Central Ltd.
- id
- 164396b4-4adb-4515-82f8-75c06506d450
- date added to LUP
- 2023-02-07 08:49:35
- date last changed
- 2025-04-05 05:08:56
@article{164396b4-4adb-4515-82f8-75c06506d450,
abstract = {{<p>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.</p>}},
author = {{Boza-Serrano, Antonio and Reyes, Juan F. and Rey, Nolwen L. and Leffler, Hakon and Bousset, Luc and Nilsson, Ulf and Brundin, Patrik and Venero, Jose Luis and Burguillos, Miguel Angel and Deierborg, Tomas}},
issn = {{2051-5960}},
keywords = {{Galectin-3; Microglia; Neuroinflammation; Parkinson's disease; α-synuclein}},
language = {{eng}},
month = {{01}},
publisher = {{BioMed Central (BMC)}},
series = {{Acta Neuropathologica Communications}},
title = {{The role of Galectin-3 in α-synuclein-induced microglial activation}},
url = {{http://dx.doi.org/10.1186/s40478-014-0156-0}},
doi = {{10.1186/s40478-014-0156-0}},
volume = {{2}},
year = {{2014}},
}