Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia

By Changyoun Kim, D. Ho, Ji-Eun Suk, S. You, Sarah Michael, Junghee Kang, Sung Joong Lee, E. Masliah, D. Hwang, He‐Jin Lee and 1 more. Nature Communications, 2013

813 citations recorded by the source corpus.

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. Parkinson’s disease is associated with the accumulation of abnormal aggregates of α-synuclein and microglial neuroinflammation. Kim et al. show that α-synuclein oliogomers released by neurons activate microglia by stimulating Toll-like receptor 2 signalling in these cells.

Subfields: Cellular and Molecular Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/ec9bafee27c1d37dc5ab0e83fdc38c78954a7468

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In Cellular and Molecular Neuroscience

1. M. Mouradian
2. V. Dias
3. Viviana Gradinaru
4. E. Junn

In Neurology

1. M. Mouradian
2. V. Dias
3. Chao Gao
4. Shengdi Chen
5. Yuyan Tan
6. Jingwen Jiang
7. E. Junn

Citations in the corpus

• Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease (2016, positive): “, 2016), and αSyn aggregates activate immune cells, including brain-resident microglia (Kim et al., 2013; Sanchez-Guajardo et al., 2013).”
• Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response (2018, background): “Further, activation of another TLR—tolllike receptor 2 (TLR2), which can be also stimulated by fibrillar Aβ, has a detrimental impact on microglia activating the cells into a more pro-inflammatory profile (Dansokho and Heneka, 2017).”
• Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023, background): “Oligomeric α-syn directly engages TLR1/2 and TLR4 to induce a pro-inflammatory M1 phenotype.(246,247) CD36 and P2X7 receptors are also involved in microglial activation induced by α-syn.”
• Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis (2019, background): “Combination of TLR2 with α-synuclein promotes downstream neurotoxic signals involving MyD88 and NF-κB, resulting in the production of TNF and IL-1β [161, 162].”
• The Role of Oxidative Stress in Parkinson’s Disease (2013, background): “In this regard, evidence has been presented for oligomeric alpha-synuclein as an agonist for tolllike receptor 2 (TLR2) and the importance of this signaling pathway in microglia activation [281].”