title: Activation of MyD88-dependent TLR1/2 signaling by misfolded α-synuclein, a protein linked to neurodegenerative disorders.
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.
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Stefano G
authors.initials: SG
authors.lastname: Daniele
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA. Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Béraud
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Connor
authors.initials: C
authors.lastname: Davenport
authors.affiliation: 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.
authors.forename: Kui
authors.initials: K
authors.lastname: Cheng
authors.affiliation: 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.
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
authors.affiliation: 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.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Maguire-Zeiss
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D020961:Lewy Body Disease / Q000235:genetics / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051194:Toll-Like Receptor 1 / Q000235:genetics / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C497604:SNCA protein, human; C497605:Snca protein, mouse; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051844:alpha-Synuclein