Stefano G Daniele1, Dawn Béraud2, Connor Davenport1, Kui Cheng3, Hang Yin4, Kathleen A Maguire-Zeiss5. 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.
Synucleinopathies, such as pan class="Disease">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.
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