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

Nat Commun. 2013;4:1562. doi: 10.1038/ncomms2534.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chemokines / metabolism
  • Chromatography, Gel
  • Dopaminergic Neurons / metabolism
  • Humans
  • Immunohistochemistry
  • Lewy Body Disease / metabolism
  • Lewy Body Disease / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / metabolism*
  • Microglia / pathology
  • Neurons / metabolism*
  • Paracrine Communication*
  • Protein Conformation
  • Protein Structure, Quaternary
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Toll-Like Receptor 2 / agonists*
  • Toll-Like Receptor 2 / chemistry
  • Toll-Like Receptor 2 / metabolism
  • Up-Regulation
  • alpha-Synuclein / chemistry*
  • alpha-Synuclein / metabolism*

Substances

  • Chemokines
  • Toll-Like Receptor 2
  • alpha-Synuclein