ArticleProceedings of the National Academy of Sciences of the United States of America2021
Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers, 1 of them a synthesis that pooled it.
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Who cites it
91 citing papers in PubMed, 1 synthesis or guideline pooled it, 132 citations in OpenAlex.
- Pre-clinical Studies Identifying Molecular Pathways of Neuroinflammation in Parkinson's Disease: A Systematic Review.Frontiers in aging neuroscience · 2022Pooled it
- From mitochondria to innate immunity: The mtDNA-driven cGAS/STING-NLRP3 cascade and its therapeutic implications in neurodegenerative diseases (Review).Experimental and therapeutic medicine · 2026Review
- Brain region-resolved pharmacodynamics of an antisense oligonucleotide targeting human SNCA 3'UTR in BAC-hSNCA rats.Translational neurodegeneration · 2026Article
- The Gut-Immune-Brain Axis in Aging: Integrating Immunosenescence, Inflammaging, and Neuroinflammation for Precision Medicine.Medical sciences (Basel, Switzerland) · 2026Review
- Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer's disease brain.Cell chemical biology · 2026Article
- The mitophagy-inflammasome axis: a shared pathological hub in Alzheimer's and Parkinson's diseases.Translational neurodegeneration · 2026Review
- VlPAG/DRN Microglia Drive Neuropathic Pain-Induced Depression via a Defined Neuroimmune Axis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- iPSC-Derived Microglia-like Cells Exhibit Protocol-Dependent Transcriptomic Features and Robust Phagocytosis of Glioma Cells.bioRxiv : the preprint server for biology · 2026Article
- TNF-α induces type I IFN signalling to suppress neurogenesis and recruit T cells.Nature communications · 2026Article
- Single nuclear RNA sequencing shows altered microglial and astrocytic functions in post-mortem Parkinson's disease tissue.BMC genomic data · 2026Article
- Exercise Intervention for REM Sleep Behavior Disorder in Parkinson's Disease: Mechanisms and Implications for Neurorehabilitation.CNS neuroscience & therapeutics · 2026Review
- Using iPSC models to examine neuron-glia interactions in neurodegenerative diseases.Bioscience reports · 2026Review
- PET-MRI biomarkers reveal efficacy of a novel NLRP3 inhibitor in Parkinson's disease models.Brain : a journal of neurology · 2026Article
- Mitochondrial Dysfunction in the Inflammatory Process of Neurodegenerative Diseases.Biomedicines · 2026Review
- Microglia-associated progression of multiple sclerosis: target identification and therapeutic engagement in human in vitro models.Experimental & molecular medicine · 2026Review
- Single-cell analysis of the peripheral immune landscape in Parkinson's disease: insights into dendritic cell and CD4+ T-cell transcriptomics.NPJ Parkinson's disease · 2026Article
- Engineering a Perfusion Bioreactor System for hiPSC-Derived Progenitor Co-Culture Capturing Microglial Features in CNS Development.Biotechnology and bioengineering · 2026Article
- Glial Cells as Key Mediators in the Pathophysiology of Neurodegenerative Diseases.International journal of molecular sciences · 2026Review
- Microglia, Astrocytes, and Oligodendrocytes in Parkinson's Disease: Neuroinflammatory Crosstalk and Emerging Therapeutic Strategies.Biomolecules · 2026Review
- Mitophagy-NLRP3 Inflammasome Crosstalk in Parkinson's Disease: Pathogenic Mechanisms and Emerging Therapeutic Strategies.International journal of molecular sciences · 2026Review
31 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 5 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.