Increased Immune Activation by Pathologic α‐Synuclein in Parkinson's Disease
Open accessAbstract
Objective: Excessive inflammation in the central nervous system (CNS) and the periphery can result in neurodegeneration and parkinsonism. Recent evidence suggests that immune responses in Parkinson disease patients are dysregulated, leading to an increased inflammatory reaction to unspecific triggers. Although α‐synuclein pathology is the hallmark of Parkinson disease, it has not been investigated whether pathologic α‐synuclein is a specific trigger for excessive inflammatory responses in Parkinson disease. Methods: We investigated the immune response of primary human monocytes and a microglial cell line to pathologic forms of α‐synuclein by assessing cytokine release upon exposure. Results: We show that pathologic α‐synuclein (mutations, aggregation) results in a robust inflammatory activation of human monocytes and microglial BV2 cells. The activation is conformation‐ dependent, with increasing fibrillation and early onset mutations having the strongest effect on immune activation. We also found that activation of immune cells by extracellular α‐synuclein is potentiated by extracellular vesicles, possibly by facilitating the uptake of α‐synuclein. Blood extracellular vesicles from Parkinson disease patients induce a stronger activation of monocytes than blood extracellular vesicles from healthy controls. Most importantly, monocytes from Parkinson disease patients are dysregulated and hyperactive in response to stimulation with pathologic α‐synuclein. Furthermore, we demonstrate that α‐synuclein pathology in the CNS is sufficient to induce the monocyte dysregulation in the periphery of a mouse model. Interpretation: Taken together, our data suggest that α‐synuclein pathology and dysregulation of monocytes in Parkinson disease can act together to induce excessive inflammatory responses to α‐synuclein. ANN NEUROL 2019;86:593–606
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Extracellular α-synuclein can activate microglia or astrocytes through binding to specific surface receptors (e.g., TLRs, FcγR) or intracellular receptors (e.g., NLRP3).
“This extracellular α-synuclein can further activate microglia or astrocytes through binding to the specific surface receptors (e.g., TLRs, FcγR) or to intracellular receptors (e.g., NLRP3).49,63,64”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [63]
The section “Cellular Uptake Is Important for Immune Cell Activation by EV-Associated α-syn” (page not provided) reports activation of BV2 microglia and a trend toward reduced monocyte activation when TLR2 or TLR4 was blocked. Figure 4 specifies that the TLR reductions were not statistically significant. The paper does not establish activation of astrocytes or binding through FcγR or NLRP3. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDifferent human α-syn fibril structures can elicit powerful immunological responses, especially from myeloid cells like microglia and monocyte-derived macrophages.
“Previous studies have suggested that different human α-syn fibril structures can elicit powerful immunological responses, especially from myeloid cells like microglia and monocyte-derived macrophages [MDMs; (74, 75)].”
From Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases (2024) · cites this paper as [74]
In “α-syn Pathology Enhances the Activation of Innate Immune Cells by α-syn” (page unavailable), the paper reports that distinct recombinant human α-syn fibril structures activate blood monocytes and BV2 microglial cells to different extents, with mature fibrils producing a strong response. Its Cell Culture section (page unavailable) identifies the human cells as isolated blood monocytes, not monocyte-derived macrophages; BV2 is a microglial cell line. The claim is supported for fibril-dependent immune activation, but not for the specified macrophage population. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAt least one study identified human α-syn fibrils as the most potent in inducing secretion of proinflammatory cytokines and chemokines.
“at least one study identified human α-syn fibrils as the most potent in inducing the secretion of proinflammatory cytokines and chemokines (74).”
From Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases (2024) · cites this paper as [74]
The Figure 2 caption reports that mature recombinant human wild-type α-syn fibrils induced the strongest cytokine response among the tested forms in monocytes and BV2 cells; it identifies IL-6 release as the measure. The cited passages do not establish that fibrils were also the most potent at inducing chemokine secretion. (LLM, conf=0.87)
Experimental — accuracy not yet measured
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References 55 · Cited by 161
Research works printed but not linked: 39
- Harms AS, Delic V, Thome AD, et al. alpha-Synuclein fibrils recruit peripheral immune cells in the rat brain prior to neurodegeneration. Acta Neuropathol Commun 2017;5:85.
- Byler SL, Boehm GW, Karp JD, et al. Systemic lipopolysaccharide plus MPTP as a model of dopamine loss and gait instability in C57Bl/6J mice. Behav Brain Res 2009;198:434-439.
- Ouchi Y, Yoshikawa E, Sekine Y, et al. Microglial activation and dopamine terminal loss in early Parkinson's disease. Ann Neurol 2005;57:168-175.
- Cunningham C, Wilcockson DC, Campion S, et al. Central and sys- temic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neu- rodegeneration. J Neurosci 2005;25:9275-9284.
- Bliederhaeuser C, Grozdanov V, Speidel A, et al. Age-dependent defects of alpha-synuclein oligomer uptake in microglia and mono- cytes. Acta Neuropathol 2016;131:379-391.
- Pieri L, Madiona K, Melki R. Structural and functional properties of prefibrillar α-synuclein oligomers. Sci Rep 2016;6:24526.
- Danzer KM, Haasen D, Karow AR, et al. Different species of alpha- synuclein oligomers induce calcium influx and seeding. J Neurosci 2007;27:9220-9232.
- Bousset L, Pieri L, Ruiz-Arlandis G, et al. Structural and functional characterization of two alpha-synuclein strains. Nat Commun 2013;4: 2575.
- Gath J, Bousset L, Habenstein B, et al. Yet another polymorph of alpha-synuclein: solid-state sequential assignments. Biomol NMR Assign 2014;8:395-404.
- Makky A, Bousset L, Polesel-Maris J, Melki R. Nanomechanical prop- erties of distinct fibrillar polymorphs of the protein alpha-synuclein. Sci Rep 2016;6:37970.
- Gath J, Bousset L, Habenstein B, et al. Unlike twins: an NMR com- parison of two alpha-synuclein polymorphs featuring different toxic- ity. PLoS One 2014;9:e90659.
- Gath J, Habenstein B, Bousset L, et al. Solid-state NMR sequen- tial assignments of alpha-synuclein. Biomol NMR Assign 2012;6: 51-55.
- Schuck P. Size-distribution analysis of macromolecules by sedimenta- tion velocity ultracentrifugation and lamm equation modeling. Biophys J 2000;78:1606-1619.
- Schuck P, Perugini MA, Gonzales NR, et al. Size-distribution analysis of proteins by analytical ultracentrifugation: strategies and applica- tion to model systems. Biophys J 2002;82:1096-1111.
- Danzer KM, Kranich LR, Ruf WP, et al. Exosomal cell-to-cell transmis- sion of alpha synuclein oligomers. Mol Neurodegener 2012;7:42.
- Hoffmeister M, Krieg J, Ehrke A, et al. Developmental neurogenesis in mouse and Xenopus is impaired in the absence of Nosip. Dev Biol 2017;429:200-212.
- Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods 2012;9:671-675.
- Ashburner M, Ball CA, Blake JA, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 2000;25:25-29.
- Zarranz JJ, Alegre J, Gomez-Esteban JC, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004;55:164-173.
- Lesage S, Anheim M, Letournel F, et al. G51D alpha-synuclein muta- tion causes a novel parkinsonian-pyramidal syndrome. Ann Neurol 2013;73:459-471.
- Appel-Cresswell S, Vilarino-Guell C, Encarnacion M, et al. Alpha- synuclein p.H50Q, a novel pathogenic mutation for Parkinson's dis- ease. Mov Disord 2013;28:811-813.
- Proukakis C, Dudzik CG, Brier T, et al. A novel alpha-synuclein missense mutation in Parkinson disease. Neurology 2013;80: 1062-1064.
- Singleton AB, Farrer MJ, Bonifati V. The genetics of Parkinson's disease: progress and therapeutic implications. Mov Disord 2013;28:14-23.
- Kamiyoshihara T, Kojima M, Ueda K, et al. Observation of multiple intermediates in alpha-synuclein fibril formation by singular value decomposition analysis. Biochem Biophys Res Commun 2007;355: 398-403.
- Lee HJ, Patel S, Lee SJ. Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci 2005;25:6016-6024.
- Zondler L, Feiler MS, Freischmidt A, et al. Impaired activation of ALS monocytes by exosomes. Immunol Cell Biol 2017;95:207-214.
- Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997;276:2045-2047.
- Kruger R, Kuhn W, Muller T, et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 1998;18: 106-108.
- Shi M, Liu C, Cook TJ, et al. Plasma exosomal alpha-synuclein is likely CNS-derived and increased in Parkinson's disease. Acta Neuro- pathol 2014;128:639-650.
- Cerri S, Ghezzi C, Sampieri M, et al. The exosomal/total alpha- synuclein ratio in plasma is associated with glucocerebrosidase activ- ity and correlates with measures of disease severity in PD patients. Front Cell Neurosci 2018;12:125.
- Zhao ZH, Chen ZT, Zhou RL, et al. Increased DJ-1 and alpha- synuclein in plasma neural-derived exosomes as potential markers for Parkinson's disease. Front Aging Neurosci 2018;10:438.
- Sulzer D, Alcalay RN, Garretti F, et al. T cells from patients with Parkinson's disease recognize alpha-synuclein peptides. Nature 2017;546:656-661.
- Hamza TH, Zabetian CP, Tenesa A, et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet 2010;42:781-785.
- Chen H, Jacobs E, Schwarzschild MA, et al. Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease. Ann Neurol 2005;58:963-967.
- Zondler L, Muller K, Khalaji S, et al. Peripheral monocytes are func- tionally altered and invade the CNS in ALS patients. Acta Neuro- pathol 2016;132:391-411.
- Bliederhaeuser C, Zondler L, Grozdanov V, et al. LRRK2 contributes to monocyte dysregulation in Parkinson's disease. Acta Neuropathol Commun 2016;4:123.
- Hoffmann A, Ettle B, Bruno A, et al. Alpha-synuclein activates BV2 microglia dependent on its aggregation state. Biochem Biophys Res Commun 2016;479:881-886.
- Alvarez-Erviti L, Seow Y, Schapira AH, et al. Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmis- sion. Neurobiol Dis 2011;42:360-367.
- Matsumoto J, Stewart T, Sheng L, et al. Transmission of alpha-syn- uclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: another mechanism for initiation and progression of Parkinson's disease? Acta Neuropathol Commun 2017;5:71.
- Authors
- Grozdanov, V., Bousset, L., Hoffmeister, M., Bliederhaeuser, C., Meier, C., Madiona, K., Pieri, L., Kiechle, M., McLean, P. J., Kassubek, J., Behrends, C., Ludolph, A. C., Weishaupt, J. H., Melki, R., & Danzer, K. M.
- Affiliations
- Universität Ulm (DE)
- Centre National de la Recherche Scientifique (FR)
- Goethe University Frankfurt (DE)
- Mayo Clinic (US)
- Munich Cluster for Systems Neurology (DE)
- Corresponding author
- Danzer, Karin M.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2019-08-15
- Volume
- 86
- Issue
- 4
- Pages
- 593-606
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2964045944
- Cited by
- 161
- References
- 55
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 29 · 2023: 17 · 2022: 31 · 2021: 25 · 2020: 19 · 2019: 1
- FWCI
- 12.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of Neurology (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by-nc)
- mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
- OPen Access Repositorium der Universität Ulm (OPARU) (Ulm University) (submittedVersion, other-oa)
- DZNE Pub (submittedVersion, cc-by-nc)
- Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by-nc)
- Universität Ulm, Kommunikations- und Informationszentrum (kiz)
- Funders
- Boehringer Ingelheim Stiftung
- Centre National de la Recherche Scientifique (European Commission Joint Programme on Neurodegene)
- Deutsche Forschungsgemeinschaft (Collaborative Research Center (CRC1177), Emmy Noether group, Munich Cluster for Systems Neurology (EXC2145 SyNergy))
- Fondation Bettencourt Schueller
- Fondation Simone et Cino Del Duca
- Fondation Thierry Latran
- Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg (Junior professorship program)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, alpha-synuclein, immune activation, neuroinflammation, monocytes, microglia, extracellular vesicles, alpha-synuclein aggregation, alpha-synuclein mutations, cytokine production, mouse model
- MeSH terms
- Extracellular Vesicles, Animals, Cells, Cultured, Humans, Inflammation, Mice, Transgenic, Monocytes, Mutation, Parkinson Disease, Cytokines, Microglia, Mice, alpha-Synuclein
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