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

Acta Neuropathologica
Craig D HughesDavid Klenerman

Abstract

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-α 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.

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Citations

Aug 30, 2019·Fluids and Barriers of the CNS·Louise DelsingJane Synnergren
Aug 27, 2019·Movement Disorders : Official Journal of the Movement Disorder Society·Sara Konstantin NissenMarina Romero-Ramos
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Mar 5, 2021·Proceedings of the National Academy of Sciences of the United States of America·Kristine FarmenMarina Romero-Ramos
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Methods Mentioned

BETA
FCS
FRET
enzyme-linked immunosorbent assay
ELISA
fluorescence imaging

Software Mentioned

FRET
gene co - expression network analysis ( WGCNA ) R package
VEGAS
HCS
Origin
[UNK] Cell Analysis
sm
Volocity
gProfileR4 R package

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