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Microglial NLRP3 Inflammasome Activation upon TLR2 and TLR5 Ligation by Distinct α-Synuclein Assemblies
Hannah Scheiblich1,2, Luc Bousset3, Stephanie Schwartz1
1Department of Neurodegenerative Disease and Gerontopsychiatry/Neurology, University of Bonn Medical Center, Bonn, Germany.
Abstract:
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.
Insights
Parkinson's disease involves abnormal alpha-synuclein (α-syn) protein. Microglia immune cells activate the NLRP3 inflammasome, hindering α-syn clearance, but NLRP3 inhibition improves its degradation.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Parkinson's disease (PD) is a neurodegenerative disorder linked to abnormal alpha-synuclein (α-syn) aggregation.
- Microglia, the brain's immune cells, respond to misfolded proteins via pattern recognition receptors and signaling pathways.
Purpose of the Study:
- To investigate how different forms of α-syn activate primary microglia.
- To understand the role of the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome in α-syn clearance by microglia.
Main Methods:
- Primary microglia isolated from wild-type mice were exposed to distinct α-syn forms (monomers and oligomers).
- Activation of the NLRP3 inflammasome was assessed, along with α-syn internalization and degradation.
- The effects of NLRP3 inhibition (using CRID3 sodium salt) and NLRP3 deficiency on α-syn clearance were evaluated.
Main Results:
- Both α-syn monomers and oligomers activated the NLRP3 inflammasome through TLR2 and TLR5 ligation.
- Microglia efficiently internalized α-syn but showed impaired degradation.
- NLRP3 inhibition and deficiency significantly enhanced the clearance of α-syn oligomers.
Conclusions:
- Distinct α-syn forms differentially activate microglial NLRP3 inflammasome signaling.
- This activation compromises α-syn degradation, contributing to PD pathology.
- Inhibiting NLRP3 presents a potential therapeutic strategy to improve α-syn clearance in Parkinson's disease.
