Journal
SCIENCE SIGNALING
Volume 8, Issue 376, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2005965
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Funding
- Parkinson's Disease Foundation Summer Student Fellowship [PDF-SFW-1350]
- NIH/National Institute of Neurological Disorders and Stroke [T32NS041218]
- NIH [R01GM101279]
- NIH/National Institute of Environmental Health Sciences [R01ES014470]
- Parkinson's Movement Disorder Foundation
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Synucleinopathies, such as Parkinson's disease and diffuse Lewy body disease, are progressive neurodegenerative disorders characterized by selective neuronal death, abnormal accumulation of misfolded alpha-synuclein, and sustained microglial activation. In addition to inducing neuronal toxicity, higher-ordered oligomeric alpha-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 alpha-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-kappa B (nuclear factor kappa B) and the increased production of the proinflammatory cytokines TNF-alpha (tumor necrosis factor-alpha) and IL-1 beta (interleukin-1 beta) 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-kappa B and secretion of TNF-alpha 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 alpha-synuclein, supporting the possibility of repurposing this drug for synucleinopathies.
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