Abstract
BackgroundThe pathological hallmarks of Parkinson’s disease are intracellular inclusions composed mainly of misfolded α-synuclein (αSYN). Under physiological conditions αSYN is mostly localized in synapses. In addition, a portion of αSYN is secreted to the extracellular space, where it may be sequestered by neighboring cells and could induce inflammatory responses. The mechanisms of αSYN 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 αSYN produced in bacteria.ResultsThe mRNA induction of pro-inflammatory cytokines, inducible nitric oxide synthase and cyclooxygenase-2 was significantly reduced in TLR4 knockout astrocytes. The αSYN-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 κB was abolished in TLR4 knockout astrocytes. In contrast, the uptake of exogenous αSYN was unaffected by TLR4 knockout.ConclusionsExtracellular αSYN can activate pro-inflammatory TLR4 pathways in astrocytes, whereas αSYN uptake is independent of TLR4.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-015-0192-0) contains supplementary material, which is available to authorized users.
Highlights
The pathological hallmarks of Parkinson’s disease are intracellular inclusions composed mainly of misfolded α-synuclein
Our results indicate that αSYN is able to activate toll-like receptor 4 (TLR4) signal transduction and thereby induces the expression of pro-inflammatory cytokines, inducible nitric oxide (NO) synthase (Nos2) and Cox-2, to mediate nuclear translocation of nuclear factor κB (NF-κB) and to activate c-Jun N-terminal kinase (JNK) and p38 mitogenactivated protein kinase (MAPK) modules
Treatment with recombinant αSYN induces TLR4‐dependent gene expression in primary astrocyte cultures To investigate if TLR4 plays a role in inflammatory reactions to exogenous αSYN, primary littermate Tlr4+/+ and Tlr4−/− astrocytes were treated with recombinant αSYN, and LPS as a positive control
Summary
The pathological hallmarks of Parkinson’s disease are intracellular inclusions composed mainly of misfolded α-synuclein (αSYN). Inflammation in the central nervous system is characterized by increased activation of microglia and astrocytes, elevated production of cytokines and other pro-inflammatory mediators including nitric oxide (NO) and prostaglandins, enhanced blood–brain-barrier permeability and increased leukocyte invasion. Neuroinflammation is an acutely protective mechanism, long-lasting and persistent formation and accumulation of pro-inflammatory mediators can initiate neuronal damage, neuronal circuit impairments and Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, which affects approximately 1 % of the population over 65 years of age. Postmortem studies have shown an increase in neuroinflammatory signals in the brains of PD patients. The neuroinflammatory pathology found in brains of PD patients has been reproduced in several PD animal models [5]
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