{"doi":"10.1073/pnas.2025847118","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.","journal":"Proceedings of the National Academy of Sciences","year":2021,"id":148136,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":135,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9526,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":36101,"name":"Kristopher L. Nazor","orcid":"0000-0001-7606-157X","position":1,"is_corresponding":false},{"id":630309,"name":"Yvonne S. Eisele","orcid":"0000-0002-3868-4327","position":2,"is_corresponding":false},{"id":630310,"name":"Titas Grabauskas","orcid":"0000-0002-3512-9862","position":3,"is_corresponding":false},{"id":300266,"name":"Nima Dolatabadi","orcid":null,"position":4,"is_corresponding":false},{"id":630311,"name":"James Parker","orcid":"0000-0002-1150-8374","position":5,"is_corresponding":false},{"id":298843,"name":"Abdullah Sultan","orcid":"0000-0001-8203-4391","position":6,"is_corresponding":false},{"id":630312,"name":"Zhenyu Zhong","orcid":"0000-0002-9441-7645","position":7,"is_corresponding":false},{"id":370274,"name":"Marshall S. Goodwin","orcid":null,"position":8,"is_corresponding":false},{"id":232925,"name":"Yona Levites","orcid":"0000-0001-6925-4525","position":9,"is_corresponding":false},{"id":107091,"name":"Todd E. Golde","orcid":"0000-0003-1867-7071","position":10,"is_corresponding":false},{"id":249877,"name":"Jeffery W. Kelly","orcid":"0000-0001-8943-3395","position":11,"is_corresponding":false},{"id":451714,"name":"Michael R. Sierks","orcid":"0000-0001-7301-230X","position":12,"is_corresponding":false},{"id":51360,"name":"Nicholas J. Schork","orcid":"0000-0003-0920-5013","position":13,"is_corresponding":false},{"id":233466,"name":"Michael Karin","orcid":"0000-0002-2758-6473","position":14,"is_corresponding":false},{"id":298844,"name":"Rajesh Ambasudhan","orcid":"0000-0002-9575-5961","position":15,"is_corresponding":false},{"id":292124,"name":"Stuart A. Lipton","orcid":"0000-0002-3490-1259","position":16,"is_corresponding":false},{"id":298842,"name":"Dorit Trudler","orcid":"0000-0002-5835-3322","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-18T23:42:41.063423Z","pmid":"33833060","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}