Journal
NATURE COMMUNICATIONS
Volume 4, Issue -, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/ncomms2534
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Funding
- Mid-career Research Program [2010-0015188]
- Bio and Medical Technology Development Program [2007-2004303]
- NRF [331-2007-1-C00214]
- Korean government (MEST)
- NIH [AG18440, AG5131]
- National Research Foundation of Korea [2010-0015188] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Abnormal aggregation of alpha-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 alpha-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 alpha-synuclein is conformation-sensitive; only specific types of oligomer can interact with and activate TLR2. This paracrine interaction between neuron-released oligomeric alpha-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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