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

BMC Neuroscience

Research Article

Stephanie S. Weber¹  Emmy H. Rannikko²  Philipp J. Kahle³ 

[1] Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Faculty of Medicine, Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried Müller Str. 27, 72076, Tübingen, Germany;Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Faculty of Medicine, Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried Müller Str. 27, 72076, Tübingen, Germany;Division of Translational Alzheimer Neurobiology, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden;Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Faculty of Medicine, Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried Müller Str. 27, 72076, Tübingen, Germany;German Center for Neurodegenerative Diseases, Tübingen, Germany;

关键词: Synuclein;    Toll-like receptor TLR4;    Neuroinflammation;    Cytokines;    Nitric oxide synthase;    Cyclooxygenase;    MAP kinases;    NF-κB;    Endocytosis;    Astrocytes;   

DOI  :  10.1186/s12868-015-0192-0

 received in 2015-01-14, accepted in 2015-08-13,  发布年份 2015

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Rannikko et al. 2015