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 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 synucleinopathie

Loss of One Engrailed1 Allele Enhances Induced α-Synucleinopathy

Parkinson’s disease (PD) is a synucleinopathy that has multiple neuropathological characteristics, with nigrostriatal dopamine system degeneration being a core feature. Current models of PD pathology typically fail to recapitulate several attributes of the pathogenic process and neuropathology. We aimed to define the effects of combining a mouse model exhibiting multiple PD-like changes with intrastriatal injections of α-synuclein (α-syn) pre-formed fibril (PFFs) aggregates. We employed the heterozygous Engrailed 1 (En1+/–) mouse that features several pathophysiological hallmarks of clinical PD.La enfermedad de Parkinson (EP) es una sinucleinopatía que tiene múltiples características neuropatológicas, siendo la degeneración del sistema dopaminérgico nigroestriatal una característica central. Los modelos actuales de patología de la EP generalmente no logran recapitular varios atributos del proceso patogénico y la neuropatología. Nuestro objetivo fue definir los efectos de combinar un modelo de ratón que presentaba múltiples cambios similares a los de la EP con inyecciones intraestriatales de agregados de fibrillas preformadas (PFF) de α-sinucleína (α-syn). Empleamos el ratón heterocigoto Engrailed 1 (En1+/–) que presenta varias características fisiopatológicas de la EP clínica

Alpha-synuclein aggregation and propagation in synucleinopathies; influence of the structure of aggregates

International audienc

Conformational strains of α-synuclein: Role of their interactors on alpha-synuclein pathology transmission in synucleinopathies.

International audienc

Selectivity of alpha-synuclein pathology transmission in synucleinopathies: role of alpha-synuclein strains and their interactomes?

International audienceAimsIn synucleinopathies alpha-synuclein (asyn) aggregates and spreads in the brain in a prion-like manner, affecting different cells populations and brain regions depending on the disease, and leading to distinct histopathological and clinical features. However the mechanisms underlying the selective vulnerability and tropism for different cell populations remain unknown. We know that αsyn can misfold and acquire different conformations, generating polymorphs / strains that can propagate. These strains can be produced in vitro but also amplified from human brains with synucleinopathies. We have previously demonstrated that different strains (produced in vitro or amplified from post-mortem brain tissue) are able to propagate differently in cell culture and in rodents brains. We now hypothesize that the selectivity of pathological asyn for specific cellular populations relies notably on strain-specific interactions with intracellular and membrane proteins.MethodsUsing proteomic approaches, we investigate strain-specific interactomes in different cellular populations.ResultsWe have identified specific interactomes for different asyn strains as well as common interactors for all strains.ConclusionsOur aim is to determine which interactions play key roles in strain-specific and selective propagation of pathological αsyn, and to select potential interactors to target in order to prevent or limit the transmission/amplification of αsyn strains

Selectivity of alpha-synuclein pathology transmission in synucleinopathies: role of alpha-synuclein strains and their interactomes ?

International audienceIn synucleinopathies alpha-synuclein (αsyn) aggregates and spreads in the brain in a prion-like manner, affecting different cells and brain regions depending on the disease ; resulting in distinct histopathological and clinical features. However the mechanisms underlying the selective vulnerability and tropism for different cell populations remain unknown. We know that αsyn can misfold and acquire different conformations, generating polymorphs / strains that can propagate. These strains can be produced in vitro but also amplified from human brains with synucleinopathies. We have previously demonstrated that different strains (produced in vitro or amplified from post-mortem brain tissue) are able to propagate differently in cell culture and in rodents brains. We now hypothesize that the selectivity of pathological asyn for specific cellular populations relies notably on strain-specific interactions with intracellular and membrane proteins. Using proteomic approaches, we investigate strain-specific interactomes in different cellular populations. Our aim is to determine which interactions play key roles in strain-specific and selective propagation of pathological αsyn, and to select potential interactors to target in order to prevent or limit the transmission/ amplification of αsyn strains

Identifier de nouvelles cibles moléculaires pour mieux comprendre la maladie de Parkinson

Poster vulgarisé à destination du public dans le cadre des journées Park'coeur organisées par France Parkinso

Identifier de nouvelles cibles moléculaires pour mieux comprendre la maladie de Parkinson

Poster vulgarisé à destination du public dans le cadre des journées Park'coeur organisées par France Parkinso