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Nat. Commun., Published 05 March 2013, 4, Article number: 1562 | doi:10.1038/ncomms2534 Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia

Abstract

Changyoun Kim^1,2, Dong-Hwan Ho^1,2, Ji-Eun Suk^1,2, Sungyong You³, Sarah Michael⁴, Junghee Kang⁵, Sung Joong Lee⁵, Eliezer Masliah⁴, Daehee Hwang³, He-Jin Lee^2,6 & Seung-Jae Lee^1,2

¹Department of Biomedical Science and Technology, Konkuk University, Seoul 143-701, Republic of Korea. ² SMART-IABS, Konkuk University, Seoul 143-701, Korea. ³ School of Interdisciplinary Bioscience and Bioengineering, and Department of Chemical Engineering, POSTECH, Pohang 790-784, Korea. ⁴ Department of Neurosciences and Pathology, School of Medicine, University of California San Diego, La Jolla, California 92093-0624, USA. ⁵ Department of Neuroscience, School of Dentistry and Dental Research Institute, and Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 110-749, Korea. ⁶ Department of Anatomy, School of Medicine, Konkuk University, Seoul 143-701, Korea.

Correspondence to : Seung-Jae Lee

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.

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