Exogenous α-synuclein induces toll-like receptor 4 dependent inflammatory responses in astrocytes

Background: The pathological hallmarks of Parkinson's disease are intracellular inclusions composed mainly of mis-folded alpha-synuclein (alpha SYN). Under physiological conditions alpha SYN is mostly localized in synapses. In addition, a portion of alpha SYN is secreted to the extracellular space, where it may be sequestered by neighboring cells and could induce inflammatory responses. The mechanisms of alpha SYN internalization and signal transduction are not unequivocally clarified. In this work we investigated in primary mouse astrocytes the involvement of toll-like receptor 4 (TLR4) in the induction of inflammatory responses upon exposure to purified human alpha SYN produced in bacteria. Results: The mRNA induction of pro-inflammatory cytokines, inducible nitric oxide synthase and cyclooxygenase-2 was significantly reduced in TLR4 knockout astrocytes. The alpha SYN-mediated activation of c-Jun N-terminal kinases and p38 mitogen-activated protein kinase tended to be diminished, and nuclear translocation of the p65 subunit of nuclear factor kappa B was abolished in TLR4 knockout astrocytes. In contrast, the uptake of exogenous alpha SYN was unaffected by TLR4 knockout. Conclusions: Extracellular alpha SYN can activate pro-inflammatory TLR4 pathways in astrocytes, whereas alpha SYN uptake is independent of TLR4.