title: Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia.
abstract: 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.
authors: Department of Biomedical Science and Technology, Konkuk University, Seoul 143-701, Republic of Korea.
authors: Changyoun
authors: C
authors: Kim
authors: Dong-Hwan
authors: DH
authors: Ho
authors: Ji-Eun
authors: JE
authors: Suk
authors: Sungyong
authors: S
authors: You
authors: Sarah
authors: S
authors: Michael
authors: Junghee
authors: J
authors: Kang
authors: Sung
authors: S
authors: Joong Lee
authors: Eliezer
authors: E
authors: Masliah
authors: Daehee
authors: D
authors: Hwang
authors: He-Jin
authors: HJ
authors: Lee
authors: Seung-Jae
authors: SJ
authors: Lee
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D002850:Chromatography, Gel; D059290:Dopaminergic Neurons / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020961:Lewy Body Disease / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism*; D019899:Paracrine Communication; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D015854:Up-Regulation; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D018925:Chemokines; D051195:Toll-Like Receptor 2; D051844:alpha-Synuclein