Details

Autor(en) / Beteiligte

• Daniele, Stefano G
• Béraud, Dawn
• Davenport, Connor
• Cheng, Kui
• Yin, Hang
• Maguire-Zeiss, Kathleen A

Titel

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

Ist Teil von

• Science signaling, 2015-05, Vol.8 (376), p.ra45

Ort / Verlag

United States

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.