@article{85accda303f942078980b8990753aa71,
title = "Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia",
abstract = "Parkinson's disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn-antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1β (IL-1β) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-β peptide (Aβ) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia.",
keywords = "Alzheimer's disease, Antibody therapies, Lewy body dementia, Neuroinflammation, Parkinson's disease",
author = "Dorit Trudler and Nazor, {Kristopher L.} and Eisele, {Yvonne S.} and Titas Grabauskas and Nima Dolatabadi and James Parker and Abdullah Sultan and Zhenyu Zhong and Goodwin, {Marshall S.} and Yona Levites and Golde, {Todd E.} and Kelly, {Jeffery W.} and Sierks, {Michael R.} and Schork, {Nicholas J.} and Michael Karin and Rajesh Ambasudhan and Lipton, {Stuart A.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Swagata Ghatak for helpful discussions. This work was supported in part by NIH Grants R01 NS086890, RF1 AG057409, R01 AG056259, R01 DA048882, and DP1 DA041722 (to S.A.L., who holds the Step Family Foundation Endowed Chair), and R01 AI043477 and the Coins for Alzheimer{\textquoteright}s Research Trust Foundation (to M.K., who is an American Cancer Research Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases). Z.Z. was supported in part by a Cancer Research Institute Irvington Postdoctoral Fellowship, the Prevent Cancer Foundation Board of Directors Research Fund, and the American Association for the Study of Liver Diseases Pinnacle Research Award. Z.Z. is also a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar and is supported by a CPRIT New Investigator Recruitment Award (RR180014). J.W.K. and Y.S.E. were supported in part by NIH Grant R01 DK46335. Y.S.E. was supported by a K99 Pathway to Independence Award from the National Institute on Aging (K99 AG050764). D.T. was supported in part by postdoctoral fellowship grant 11721 from Autism Speaks, Inc. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = apr,
day = "13",
doi = "10.1073/pnas.2025847118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "15",
}