Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia
Open accessAbstract
Abnormal aggregation of α-synuclein and sustained microglial activation are important contributors to the pathogenic processes of Parkinson's disease. However, the relationship between disease-associated protein aggregation and microglia-mediated neuroinflammation remains unknown. Here, using a combination of in silico, in vitro and in vivo approaches, we show that extracellular α-synuclein released from neuronal cells is an endogenous agonist for Toll-like receptor 2 (TLR2), which activates inflammatory responses in microglia. The TLR2 ligand activity of α-synuclein is conformation-sensitive; only specific types of oligomer can interact with and activate TLR2. This paracrine interaction between neuron-released oligomeric α-synuclein and TLR2 in microglia suggests that both of these proteins are novel therapeutic targets for modification of neuroinflammation in Parkinson's disease and related neurological diseases.
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In animal models of PD and in PD patients, misfolded α-synuclein is released from injured neurons into extracellular fluid.
“In animal models of PD and in PD patients, misfolded α-synuclein was found to be released from injured neurons into the extracellular fluid.51,61,62”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [61]
The Abstract (page unavailable) says neurons release α-synuclein and that misfolding and aggregation may facilitate its release. The Results section on cell-released α-synuclein (page unavailable) demonstrates release from cultured neuronal cells, but reports that overexpression did not affect their viability. The paper does not establish that misfolded α-synuclein was released from injured neurons in PD animal models or PD patients. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTLR2 plays a role in neurons in response to α-synuclein.
“TLR2 also plays a role in neurons in response to α-synuclein in addition to microglia19,57,58.”
From Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration (2020) · cites this paper as [19]
The Results section on TLR2 upregulation reports TLR2 labeling in pyramidal neurons, but the α-synuclein-related increase it describes is in microglia. The in vivo Results show that α-synuclein expressed by neurons activates microglia through TLR2; they do not establish that TLR2 mediates a neuronal response to α-synuclein. Page numbers are unavailable in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredTLR2 neutralization decreases the expression of pro-inflammatory cytokines in this mouse model of synucleinopathy.
“We have previously demonstrated that although TLR2 neutralization decreases the expression of pro-inflammatory cytokines it may also impact neurotrophin production in this mouse model of synucleinopathy (7).”
From LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies (2020) · cites this paper as [7]
The Results section on α-synuclein-induced microglial activation reports that a TLR2-blocking antibody eliminated induced cytokine gene expression in isolated microglia. The in vivo Results instead report reduced microglial activation in Tlr2-deficient mice; they do not show that TLR2 neutralization decreased cytokine expression in the mouse model. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTLR2 neutralization may also impact neurotrophin production in this mouse model of synucleinopathy.
“We have previously demonstrated that although TLR2 neutralization decreases the expression of pro-inflammatory cytokines it may also impact neurotrophin production in this mouse model of synucleinopathy (7).”
From LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies (2020) · cites this paper as [7]
The Results section on α-synuclein-induced microglial activation reports that a TLR2-blocking antibody eliminated induced cytokine gene expression in isolated microglia; the in vivo Results report reduced microglial activation in Tlr2-deficient mice. Our copy does not report an effect of TLR2 neutralization on neurotrophin production in a mouse model of synucleinopathy (pages not provided). (LLM, conf=0.84)
Experimental — accuracy not yet measuredα-synuclein can activate glial cells by binding to TLR2 and enhance the spreading of α-synuclein.
“α-synuclein can also activate glial cells by binding to TLR261,294,295 and enhance the spreading of α-synuclein.70,296”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [61]
α-synuclein can trigger TLR4 or TLR2 activation in cultured glia, leading to an increase in inflammatory gene transcription.
“Previous reports showed α-synuclein can trigger TLR4 or TLR2 activation in cultured glia, which leads to an increase in inflammatory gene transcription19,40,41.”
From Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration (2020) · cites this paper as [19]
TLR2 plays a role in microglia in response to α-synuclein.
“TLR2 also plays a role in neurons in response to α-synuclein in addition to microglia19,57,58.”
From Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration (2020) · cites this paper as [19]
Neuron-released α-synuclein induces neurotoxic, pro-inflammatory microglial responses through Toll-like receptor 2 (TLR2).
“Neuron-released α-synuclein has been shown to induce neurotoxic, pro-inflammatory microglial responses through Toll-like receptor 2 (TLR2) but the molecular mechanisms involved are poorly understood.”
From LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies (2020) · cites this paper as [7]
Microglia accumulate near α-synuclein deposits and become proinflammatory via receptors that also bind Aβ, such as CD36 and TLR2.
“Microglia accumulate near α-synuclein deposits and become proinflammatory in a manner dependent on receptors that also bind Aβ, such as CD36 and TLR263–65.”
From Microglia in neurodegeneration (2018) · cites this paper as [65]
Oligomeric α-syn directly engages TLR1/2 and TLR4 to induce a pro-inflammatory M1 phenotype.
“Oligomeric α-syn directly engages TLR1/2 and TLR4 to induce a pro-inflammatory M1 phenotype.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [247]
TLR2 and TLR4 play a role in the uptake of α-syn and subsequent activation of microglia, boosting α-syn clearance by microglia.
“TLRs, including TLR2 and TLR4, are receptors expressed on microglia, which were demonstrated to play a role in the uptake of α-syn and the subsequent activation of microglia, boosting α-syn clearance by microglia.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [247]
Fibrillar, but not monomeric, α-synuclein induced NLRP3- and caspase-1-mediated IL-1β secretion in human monocytes and BV2 microglial cell line, or via TLR-2 signaling in rodent microglial cells.
“The fibrillar, but not monomeric, form of α-synuclein induced NLRP3- and caspase-1–mediated IL-1β secretion in human monocytes and BV2 microglial cell line (238), or via TLR-2 signaling pathway in rodents microglial cells (250).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [250]
Microglia phagocytose α-synuclein and become pro-inflammatory, expressing cytokines (IL1β, IL6, TNFα), ROS and COX2.
“Microglia also phagocytose α-synuclein, the constituent protein of Lewy bodies in Parkinson’s and Lewy Body dementias, and become pro-inflammatory in the process, expressing cytokines (IL1β, IL6, TNFα), reactive oxygen species (ROS) and prostaglandin synthesising cyclooxygenase 2 (COX2) [24,25,26].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [26]
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- Authors
- Kim, C., Ho, D.-H., Suk, J.-E., You, S., Michael, S., Kang, J., Joong Lee, S., Masliah, E., Hwang, D., Lee, H.-J., & Lee, S.-J.
- Affiliations
- Konkuk University (KR)
- Pohang University of Science and Technology (KR)
- University of California San Diego (US)
- Seoul National University (KR)
- Venue
- Nature Communications
- Published
- 2013-03-05
- Volume
- 4
- Issue
- 1
- Pages
- 1562-1562
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4089961
- OpenAlex
- W2141976392
- Cited by
- 856
- References
- 57
- Citations by year
- 2026: 58 · 2025: 68 · 2024: 74 · 2023: 68 · 2022: 83 · 2021: 111 · 2020: 93 · 2019: 53 · 2018: 67 · 2017: 42 · 2016: 44 · 2015: 53 · 2014: 35 · 2013: 7
- FWCI
- 26.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (AG5131, AG‐18440)
- National Institute on Aging (R37AG018440, R01AG018440, P50AG005131, AG-5131, P01AG031097, AG 18440, P01AG022074)
- National Institute of Neurological Disorders and Stroke (P01NS044233, P30NS076411, P30NS057096)
- National Institute of Environmental Health Sciences (P01ES016738)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- alpha-synuclein oligomers, TLR2, microglial activation, neuroinflammation, Parkinson's disease, paracrine signaling, microglia-neuron interaction, protein aggregation
- MeSH terms
- Animals, Cells, Cultured, Chromatography, Gel, Humans, Immunohistochemistry, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Protein Conformation, Signal Transduction, Up-Regulation, Rats, Sprague-Dawley, Microglia, Chemokines, Paracrine Communication, Protein Structure, Quaternary, Lewy Body Disease, Toll-Like Receptor 2, Mice, Rats, alpha-Synuclein, Dopaminergic Neurons
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