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Sci Signal. 2015 May 12;8(376):ra45. doi: 10.1126/scisignal.2005965.

Activation of MyD88-dependent TLR1/2 signaling by misfolded α-synuclein, a protein linked to neurodegenerative disorders.

Author information

1
Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
2
Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA. Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
3
Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80309, USA. Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing 100084, China.
4
Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80309, USA. Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing 100084, China. km445@georgetown.edu hubert.yin@colorado.edu.
5
Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA. Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA. km445@georgetown.edu hubert.yin@colorado.edu.

Abstract

Synucleinopathies, such as Parkinson's disease and diffuse Lewy body disease, are progressive neurodegenerative disorders characterized by selective neuronal death, abnormal accumulation of misfolded α-synuclein, and sustained microglial activation. In addition to inducing neuronal toxicity, higher-ordered oligomeric α-synuclein causes proinflammatory responses in the brain parenchyma by triggering microglial activation, which may exacerbate pathogenic processes by establishing a chronic neuroinflammatory milieu. We found that higher-ordered oligomeric α-synuclein induced a proinflammatory microglial phenotype by directly engaging the heterodimer TLR1/2 (Toll-like receptor 1 and 2) at the cell membrane, leading to the nuclear translocation of NF-κB (nuclear factor κB) and the increased production of the proinflammatory cytokines TNF-α (tumor necrosis factor-α) and IL-1β (interleukin-1β) in a MyD88-dependent manner. Blocking signaling through the TLR1/2 heterodimer with the small-molecule inhibitor CU-CPT22 reduced the nuclear translocation of NF-κB and secretion of TNF-α from cultured primary mouse microglia. Candesartan cilexetil, a drug approved for treating hypertension and that inhibits the expression of TLR2, reversed the activated proinflammatory phenotype of primary microglia exposed to oligomeric α-synuclein, supporting the possibility of repurposing this drug for synucleinopathies.

PMID:
25969543
PMCID:
PMC4601639
DOI:
10.1126/scisignal.2005965
[Indexed for MEDLINE]
Free PMC Article

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