[en] Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder and is characterized by the formation of cellular inclusions inside neurons that are rich in an abnormal form of the protein α-synuclein (α-syn). Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of signaling transduction pathways. Here, we studied activation of primary microglia isolated from wild-type mouse by distinct α-syn forms and their clearance. Internalization of α-syn monomers and oligomers efficiently activated the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome via TLR2 and TLR5 ligation, thereby acting on different signaling checkpoints. We found that primary microglia effectively engulf α-syn but hesitate in its degradation. NLRP3 inhibition by the selective inhibitor CRID3 sodium salt and NLRP3 deficiency improved the overall clearance of α-syn oligomers. Together, these data show that distinct α-syn forms exert different microglial NLRP3 inflammasome activation properties, thereby compromising its degradation, which can be prevented by NLRP3 inhibition.
Disciplines :
Neurologie
Auteur, co-auteur :
Scheiblich, Hannah ; Department of Neurodegenerative Disease and Gerontopsychiatry/Neurology, University of Bonn Medical Center, Bonn, Germany ; German Center for Neurodegenerative Diseases, Bonn, Germany
Bousset, Luc ; Institut François Jacob, MIRCen, CEA and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-aux-Roses, France, and
Schwartz, Stephanie; Department of Neurodegenerative Disease and Gerontopsychiatry/Neurology, University of Bonn Medical Center, Bonn, Germany
Griep, Angelika; German Center for Neurodegenerative Diseases, Bonn, Germany
Latz, Eicke ; Institute of Innate Immunity, University of Bonn Medical Center, Bonn, Germany
Melki, Ronald; Institut François Jacob, MIRCen, CEA and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-aux-Roses, France, and
HENEKA, Michael ; Department of Neurodegenerative Disease and Gerontopsychiatry/Neurology, University of Bonn Medical Center, Bonn, Germany, michael.heneka@ukbonn.de ; German Center for Neurodegenerative Diseases, Bonn, Germany
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
Microglial NLRP3 Inflammasome Activation upon TLR2 and TLR5 Ligation by Distinct α-Synuclein Assemblies.
EU Joint Programme - Neurodegenerative Disease Research Gemeinnützige Hertie-Stiftung Deutsche Forschungsgemeinschaft Centre National de la Recherche Scientifique Fondation pour la Recherche Médicale EU Joint Programme - Neurodegenerative Disease Research
Subventionnement (détails) :
This work was supported by the EU Joint Programme on Neurodegenerative Disease Research (JPND-SYNACTION-ANR-15-JPWG-0012-03) and by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany’s Excellence Strategy EXC2151-390873048. H.S. received funding from the Gemeinnutzige Hertie Stiftung (Hertie-Stiftung) under the Hertie Network of excellence in clinical neuroscience. R.M. and L.B. were supported by the CNRS, the EU Joint Programme on Neurodegenerative Disease Research (JPND-SYNACTION-ANR-15-JPWG-0012-03 and TransPath-ND-ANR-17-JPCD-0002-02), and the Fondation pour la Recherche Médicale (Contract DEQ. 20160334896).
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