Abstract
BackgroundParkinson’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.ResultsWe 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0156-0) contains supplementary material, which is available to authorized users.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disorder clinically typified by bradykinesia, rigidity, postural instability and tremor, as well as a wide range of non-motor symptoms including constipation, bladder dysfunction and cognitive impairment [1]
We assessed the inflammatory response by exposing microglial cells to different concentrations of monomeric or aggregated forms of α-synuclein (5, 10 and 20 μM) for 12 h, the time period at which the temporal inducible Nitric Oxide Synthase (iNOS) expression response following LPS treatment is the highest [49]
We identified a concentration-dependent upregulation of iNOS expression following both monomeric and aggregated forms of α-synuclein (Figure 1A and B, respectively)
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder clinically typified by bradykinesia, rigidity, postural instability and tremor, as well as a wide range of non-motor symptoms including constipation, bladder dysfunction and cognitive impairment [1]. While microglial activation has been suggested to play major role in the neurodegenerative process in PD [15,16], the signaling pathways that mediate this process are still poorly understood. Depending on the microenvironment/insult, activated microglia cells can adopt one of two wellcharacterized profiles, namely a classical (pro-inflammatory, M1) or an alternative (anti-inflammatory, M2) profile [21,22] In these two different states, activated microglia release different factors and express different surface proteins that allow them to sense the microenvironment and coordinate the inflammatory response. Galectin-3, which is identical to the commonly used macrophage marker Mac-2, is an inflammatory mediator known to be highly expressed in some activated inflammatory cells, including microglia. Previous studies have shown that extracellular α-synuclein aggregates can activate microglial cells, induce inflammation and contribute to the neurodegenerative process in PD. We investigated whether galectin-3 is involved in the microglia activation triggered by α-synuclein
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