Open AccessSoluble α-synuclein–antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia
Author(s) -
Dorit Trudler,
Kristopher L. Nazor,
Yvonne S. Eisele,
Titas Grabauskas,
Nima Dolatabadi,
James D. A. Parker,
Abdullah Sultan,
Zhenyu Zhong,
Marshall S. Goodwin,
Yona Levites,
Todd E. Golde,
Jeffery W. Kelly,
Michael R. Sierks,
Nicholas J. Schork,
Michael Karin,
Rajesh Ambasudhan,
Stuart A. Lipton
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2025847118
Subject(s) - inflammasome , pyrin domain , microglia , microbiology and biotechnology , neurotoxicity , caspase 1 , synucleinopathies , chemistry , receptor , antibody , inflammation , biology , alpha synuclein , biochemistry , immunology , parkinson's disease , medicine , disease , pathology , organic chemistry , toxicity
Significance Release of oligomeric/fibrillar α-synuclein (αSyn) from damaged neurons contributes to neuronal cell death in Parkinson’s disease and other neurodegenerative disorders in part via microglial activation. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving TLR2 engagement and mitochondrial damage. Oligomerized amyloid-β peptide (Aβ), as found in Alzheimer’s disease brains, exacerbates this neuroinflammation. Importantly, we found that misfolded proteins such as αSyn and Aβ, when bound to antibody and presented to hiMG, result in enhanced proinflammatory response of the NLRP3 inflammasome. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger neuroinflammation in human microglia.