Evidence map›Paper›PMID 30225556›Full record

ArticleActa neuropathologica2019

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

Craig D Hughes, Minee L Choi, Mina Ryten, Lee Hopkins, Anna Drews, Juan A Botía, Maria Iljina, Margarida Rodrigues, Sarah A Gagliano, Sonia Gandhi and 2 more

Erratum issuedOpen access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Acta neuropathologica, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 100 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
100citing papers in PubMed, 1 pooled it
10.2field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

100 citing papers in PubMed, 1 synthesis or guideline pooled it, 169 citations in OpenAlex.

  1. Pooled it
  2. Monocyte markers correlate with immune and neuronal brain changes in REM sleep behavior disorder.Proceedings of the National Academy of Sciences of the United States of America · 2021
    Trial
  3. Article
  4. Cellular and systemic modifiers of alpha-synuclein proteostasis.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026
    Review
  5. Review
  6. Article
  7. Immune-mediated excitotoxicity in brain disorders.Nature reviews. Immunology · 2026
    Review
  8. Review
  9. Article
  10. Review
  11. Immune signaling and function in neurodegeneration.The Journal of clinical investigation · 2026
    Review
  12. Review
  13. Review
  14. Review
  15. Review
  16. Article
  17. Review
  18. Review
  19. Review
  20. Article

40 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

12 authors at 4 institutions in 5 countries.

Craig D HughesDepartment of Veterinary Medicine, University of Cambridge, Cambridge, CB3 0ES, UK.
Minee L ChoiDepartment of Clinical and Movement Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Mina RytenDepartment of Molecular Neuroscience, University College London Institute of Neurology, London, WC1N 3BG, UK.
Lee HopkinsDepartment of Veterinary Medicine, University of Cambridge, Cambridge, CB3 0ES, UK.
Anna DrewsDepartment of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
Juan A BotíaDepartment of Molecular Neuroscience, University College London Institute of Neurology, London, WC1N 3BG, UK.
Maria IljinaDepartment of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
Margarida RodriguesDepartment of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
Sarah A GaglianoCenter for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
Sonia GandhiThe Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK. sonia.gandhi@ucl.ac.uk.
Clare BryantDepartment of Veterinary Medicine, University of Cambridge, Cambridge, CB3 0ES, UK. ceb27@cam.ac.uk.
David KlenermanDepartment of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK. dk10012@cam.ac.uk.ORCID http://orcid.org/0000-0001-7116-6954
University of Cambridge · GBThe Francis Crick Institute · GBUniversity College London · GBUniversity of Michigan · US

Funding

Medical Research Council MR/N008324/1Wellcome Trust
6 · The paper itself

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.

Indexed as

alpha-SynucleinAnimalsAstrocytesBrainCell DeathCytokinesHumansInflammationMicrogliaNeuronsParkinson DiseaseSubstantia NigraToll-Like Receptor 4alpha-SynucleinCytokinesToll-Like Receptor 4AggregationAlpha-synucleinInnate immunityParkinson’s diseaseTLR4

Identifiers

PMID30225556
PMCPMC6338693
OpenAlexW4235735760

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.