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Open Access 01-01-2019 | Original Paper

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

Authors: Craig D. Hughes, Minee L. Choi, Mina Ryten, Lee Hopkins, Anna Drews, Juan A. Botía, Maria Iljina, Margarida Rodrigues, Sarah A. Gagliano, Sonia Gandhi, Clare Bryant, David Klenerman

Published in: Acta Neuropathologica | Issue 1/2019

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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Title: Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis
Authors: Craig D. Hughes
Minee L. Choi
Mina Ryten
Lee Hopkins
Anna Drews
Juan A. Botía
Maria Iljina
Margarida Rodrigues
Sarah A. Gagliano
Sonia Gandhi
Clare Bryant
David Klenerman
Publication date: 01-01-2019
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 1/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-018-1907-y

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

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

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

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