Research ArticleNeurodegeneration

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

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Science Signaling  12 May 2015:
Vol. 8, Issue 376, pp. ra45
DOI: 10.1126/scisignal.2005965

Making aggregation less aggravating (to the brain)

The accumulation of aggregates of the protein α-synuclein occurs in neurodegenerative disorders called synucleinopathies, which includes Parkinson’s disease and Lewy body disease. Oligomeric α-synuclein activates proinflammatory microglia (specialized immune cells in the brain). Daniele et al. found that aggregates of α-synuclein functioned as a “danger” signal that activated the receptor complex TLR1 and TLR2 (TLR1/2) on the surface of primary mouse microglia, leading to the production of proinflammatory cytokines. Antagonists of TLR1/2, including a drug approved for hypertension, prevented the activation of microglia and cytokine secretion in response to aggregated α-synuclein. Thus, repurposing of drugs that also inhibit TLR1/2 or developing specific antagonists may be beneficial for patients with synucleinopathies.

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