Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson's disease pathogenesis

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Despite the wealth of genomic and transcriptomic data in Parkinson's disease (PD), the initial molecular events are unknown. Using LD score regression analysis, we show significant enrichment in PD heritability within regulatory sites for LPS-activated monocytes and that TLR4 expression is highest within human substantia nigra, the most affected brain region, suggesting a role for TLR4 inflammatory responses. We then performed extended incubation of cells with physiological concentrations of small alpha-synuclein oligomers observing the development of a TLR4-dependent sensitized inflammatory response with time, including TNF- production. ROS and cell death in primary neuronal cultures were significantly reduced by TLR4 antagonists revealing that an indirect inflammatory mechanism involving cytokines produced by glial cells makes a major contribution to neuronal death. Prolonged exposure to low levels of alpha-synuclein oligomers sensitizes TLR4 responsiveness in astrocytes and microglial, explaining how they become pro-inflammatory, and may be an early causative event in PD.
Publisher
SPRINGER
Issue Date
2019-01
Language
English
Article Type
Article
Citation

ACTA NEUROPATHOLOGICA, v.137, no.1, pp.103 - 120

ISSN
0001-6322
DOI
10.1007/s00401-018-1907-y
URI
http://hdl.handle.net/10203/305025
Appears in Collection
BC-Journal Papers(저널논문)
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