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U.S.A."],"published-print":{"date-parts":[[2021,4,13]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>Release of oligomeric\/fibrillar \u03b1-synuclein (\u03b1Syn) from damaged neurons contributes to neuronal cell death in Parkinson\u2019s disease and other neurodegenerative disorders in part via microglial activation. Here, we show that \u03b1Syn 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-\u03b2 peptide (A\u03b2), as found in Alzheimer\u2019s disease brains, exacerbates this neuroinflammation. Importantly, we found that misfolded proteins such as \u03b1Syn and A\u03b2, 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.<\/jats:p>","DOI":"10.1073\/pnas.2025847118","type":"journal-article","created":{"date-parts":[[2021,4,8]],"date-time":"2021-04-08T17:10:42Z","timestamp":1617901842000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":135,"title":["Soluble \u03b1-synuclein\u2013antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia"],"prefix":"10.1073","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5835-3322","authenticated-orcid":false,"given":"Dorit","family":"Trudler","sequence":"first","affiliation":[{"name":"Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037;"},{"name":"Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037;"},{"name":"Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristopher L.","family":"Nazor","sequence":"additional","affiliation":[{"name":"MYi Diagnostics &amp; 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