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Immunoregulation of microglial polarization: an unrecognized physiological function of α-synuclein

  • Li, Na1, 2
  • Stewart, Tessandra3
  • Sheng, Lifu3
  • Shi, Min3
  • Cilento, Eugene M.3
  • Wu, Yufeng2
  • Hong, Jau-Syong4
  • Zhang, Jing2, 3, 5
  • 1 Lanzhou University, Lanzhou, Gansu, 730000, China , Lanzhou (China)
  • 2 Peking University, Beijing, 100191, China , Beijing (China)
  • 3 University of Washington School of Medicine, Seattle, WA, 98104, USA , Seattle (United States)
  • 4 National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, 27709, USA , Durham (United States)
  • 5 Zhejiang University First Affiliated Hospital and School of Medicine, Hangzhou, Zhejiang, 310002, China , Hangzhou (China)
Published Article
Journal of Neuroinflammation
Springer (Biomed Central Ltd.)
Publication Date
Sep 17, 2020
DOI: 10.1186/s12974-020-01940-z
Springer Nature


BackgroundMicroglial function is vital for maintaining the health of the brain, and their activation is an essential component of neurodegeneration. There is significant research on factors that provoke “reactive” or “inflammatory” phenotypes in conditions of injury or disease. One such factor, exposure to the aggregated or oligomeric forms of α-synuclein, an abundant brain protein, plays an essential role in driving microglial activation; including chemotactic migration and production of inflammatory mediators in Lewy body (LB) diseases such as Parkinson’s disease. On the other hand, it is increasingly recognized that microglia also undergo changes, dependent on the cellular environment, that promote mainly reconstructive and anti-inflammatory functions, i.e., mostly desirable functions of microglia in a physiological state. What maintains microglia in this physiological state is essentially unknown.MethodsIn this study, using in vitro and in vivo models, we challenged primary microglia or BV2 microglia with LPS + IFN-γ, IL-4 + IL-13, α-synuclein monomer, and α-synuclein oligomer, and examined microglia phenotype and the underlying mechanism by RT-PCR, Western blot, ELISA, IF, IHC, Co-IP.ResultsWe described a novel physiological function of α-synuclein, in which it modulates microglia toward an anti-inflammatory phenotype by interaction with extracellular signal-regulated kinase (ERK) and recruitment of the ERK, nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptor γ (PPARγ) pathways.ConclusionsThese findings suggest a previously unrecognized function of monomeric α-synuclein that likely gives new insights into the pathogenesis and potential therapies for Lewy body-related diseases and beyond, given the abundance and multiple functions of α-synuclein in brain tissue.

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