Evidence map›Paper›PMID 25969543›Full record

ArticleScience signaling2015

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

Stefano G Daniele, Dawn Béraud, Connor Davenport, Kui Cheng, Hang Yin, Kathleen A Maguire-Zeiss

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Science signaling, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 175 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
175citing papers in PubMed, 1 pooled it
11.0field-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

175 citing papers in PubMed, 1 synthesis or guideline pooled it, 292 citations in OpenAlex.

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

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

6 authors at 4 institutions in 2 countries.

Stefano G DanieleDepartment of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
Dawn BéraudDepartment of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA. Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
Connor DavenportDepartment of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
Kui ChengDepartment of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80309, USA. Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing 100084, China.
Hang YinDepartment of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80309, USA. Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing 100084, China. km445@georgetown.edu hubert.yin@colorado.edu.
Kathleen A Maguire-ZeissDepartment of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA. Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA. km445@georgetown.edu hubert.yin@colorado.edu.
Georgetown University Medical Center · USGeorgetown University · USTsinghua University · CNUniversity of Colorado Boulder · US

Funding

Predoctoral Training in Intergrative NeuroscienceT32NS041231 · NINDS · GEORGETOWN UNIVERSITY · PI Ludise Malkova, Ashley S VanMeter · 2001 to 2026
$6.8M
Training in Neural Injury &PlasticityT32NS041218 · NINDS · GEORGETOWN UNIVERSITY · PI MARK P BURNS, Kathleen Anne Maguire-Zeiss · 2001 to 2026
$3.5M
Toxicant, oxidative injury, dopamine & synuclein in PDR01ES014470 · NIEHS · UNIVERSITY OF ROCHESTER · PI MAGUIRE-ZEISS, KATHLEEN ANNE · 2007 to 2011
$1.7M
Exogenous Chemical Probes of TLR-Mediated NeuroinflammationR01GM101279 · NIGMS · UNIVERSITY OF COLORADO · PI YIN, HANG HUBERT · 2013 to 2017
$1.4M
Dissecting Cell Signaling Mediated by Protein-Protein Interactions in MembranesR01GM103843 · NIGMS · UNIVERSITY OF COLORADO · PI YIN, HANG HUBERT · 2013 to 2016
$1.3M
NIEHS NIH HHS R01 ES014470NIEHS NIH HHS R01ES014470NIGMS NIH HHS R01 GM101279NIGMS NIH HHS R01GM101279NIGMS NIH HHS R01 GM103843NINDS NIH HHS T32 NS041218NINDS NIH HHS T32NS041218NINDS NIH HHS T32 NS041231
6 · The paper itself

Abstract

Synucleinopathies, such as Parkinson's disease and diffuse Lewy body disease, are progressive neurodegenerative disorders characterized by selective neuronal death, abnormal accumulation of misfolded α-synuclein, and sustained microglial activation. In addition to inducing neuronal toxicity, higher-ordered oligomeric α-synuclein causes proinflammatory responses in the brain parenchyma by triggering microglial activation, which may exacerbate pathogenic processes by establishing a chronic neuroinflammatory milieu. We found that higher-ordered oligomeric α-synuclein induced a proinflammatory microglial phenotype by directly engaging the heterodimer TLR1/2 (Toll-like receptor 1 and 2) at the cell membrane, leading to the nuclear translocation of NF-κB (nuclear factor κB) and the increased production of the proinflammatory cytokines TNF-α (tumor necrosis factor-α) and IL-1β (interleukin-1β) in a MyD88-dependent manner. Blocking signaling through the TLR1/2 heterodimer with the small-molecule inhibitor CU-CPT22 reduced the nuclear translocation of NF-κB and secretion of TNF-α from cultured primary mouse microglia. Candesartan cilexetil, a drug approved for treating hypertension and that inhibits the expression of TLR2, reversed the activated proinflammatory phenotype of primary microglia exposed to oligomeric α-synuclein, supporting the possibility of repurposing this drug for synucleinopathies.

Indexed as

Protein FoldingSignal Transductionalpha-SynucleinAnimalsHEK293 CellsHumansLewy Body DiseaseMiceMyeloid Differentiation Factor 88Parkinson DiseaseProteostasis DeficienciesToll-Like Receptor 1Toll-Like Receptor 2alpha-SynucleinMYD88 protein, humanMyd88 protein, mouseMyeloid Differentiation Factor 88SNCA protein, humanSnca protein, mouseTLR2 protein, humanTlr2 protein, mouseToll-Like Receptor 1Toll-Like Receptor 2

Identifiers

PMID25969543
PMCPMC4601639
OpenAlexW2117175402

What OpenQuestion holds

Textmetadata
LicenceTDM
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.