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

• DOI: 10.1038/ncomms2534
• Publication Date: 2013-03-05T09:45:32Z
• Authors: Changyoun Kim; Dong-Hwan Ho; Ji-Eun Suk; Sungyong You; Sarah Michael; Junghee Kang; Sung Joong Lee; Eliezer Masliah; Daehee Hwang; He-Jin Lee; Seung-Jae Lee
• Keywords: Lewy Body Disease; Neurons; 0301 basic medicine; 0303 health sciences; Protein Conformation; Dopaminergic Neurons; Mice, Transgenic; Immunohistochemistry; Toll-Like Receptor 2; Rats; 3. Good health; Mice, Inbred C57BL; Rats, Sprague-Dawley; Mice; 03 medical and health sciences; Paracrine Communication; Chromatography, Gel; Animals; Humans; Microglia; Chemokines; Protein Structure, Quaternary; Cells, Cultured; Signal Transduction

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.