Evidence map›Paper›PMID 27329107›Full record

ArticleJournal of neuroinflammation2016

Identification of a specific α-synuclein peptide (α-Syn 29-40) capable of eliciting microglial superoxide production to damage dopaminergic neurons.

Shijun Wang, Chun-Hsien Chu, Mingri Guo, Lulu Jiang, Hui Nie, Wei Zhang, Belinda Wilson, Li Yang, Tessandra Stewart, Jau-Shyong Hong and 1 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of neuroinflammation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
18citing papers in PubMed, 1 pooled it
1.3field-weighted citation impact, top 19% 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

18 citing papers in PubMed, 1 synthesis or guideline pooled it, 27 citations in OpenAlex.

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  16. Intranigral Administration ofJournal of immunology research · 2020
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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

11 authors at 6 institutions in 3 countries.

Shijun WangDepartment of Pathology, University of Washington School of Medicine, Seattle, Washington, 98104, USA.
Chun-Hsien ChuNeuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences National Institutes of Health, Research Triangle Park, NC, 27709, USA.
Mingri GuoNeuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences National Institutes of Health, Research Triangle Park, NC, 27709, USA.
Lulu JiangNeuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences National Institutes of Health, Research Triangle Park, NC, 27709, USA.
Hui NieNeuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences National Institutes of Health, Research Triangle Park, NC, 27709, USA.
Wei ZhangDepartment of Geriatrics, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
Belinda WilsonNeuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences National Institutes of Health, Research Triangle Park, NC, 27709, USA.
Li YangDepartment of Pathology, University of Washington School of Medicine, Seattle, Washington, 98104, USA.
Tessandra StewartDepartment of Pathology, University of Washington School of Medicine, Seattle, Washington, 98104, USA.
Jau-Shyong HongNeuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences National Institutes of Health, Research Triangle Park, NC, 27709, USA. hong3@niehs.nih.gov.
Jing ZhangDepartment of Pathology, University of Washington School of Medicine, Seattle, Washington, 98104, USA. zhangj@uw.edu.
National Institutes of Health · USUniversity of Washington · USCapital Medical University · CNNational Cheng Kung University · TWNational Institute of Environmental Health Sciences · USPeking University · CN

Funding

Roles Of Brain Neuroimmune System In NeurodegenerationZIAES090082 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI HONG, JAU-SHYONG SHYONG · 2009 to 2018
$22.0M
Interaction of alpha-synuclein and neurotoxicants with Mac1-NADPH oxidaseR01ES019277 · NIEHS · UNIVERSITY OF WASHINGTON · PI ZHANG, JING · 2011 to 2015
$2.0M
Microglial Phox Activity In Parkinson's DiseaseR01ES016873 · NIEHS · UNIVERSITY OF WASHINGTON · PI ZHANG, JING · 2010 to 2014
$1.7M
NIEHS NIH HHS R01 ES016873NIEHS NIH HHS R01 ES019277
6 · The paper itself

Abstract

backgroundMisfolded α-synuclein (α-Syn) aggregates participate in the pathogenesis of synucleinopathies, such as Parkinson's disease. Whereas much is known about how the various domains within full-length α-Syn (FL-α-Syn) contribute to the formation of α-Syn aggregates and therefore to their neurotoxicity, little is known about whether the individual peptides that can be generated from α-syn, possibly as intermediate metabolites during degradation of misfolded α-Syn aggregates, are neurotoxic themselves.

methodsA series of synthesized α-Syn peptides, corresponding to the locus in FL-α-Syn containing alanine 30, substitution of which with a proline causes a familial form of Parkinson's disease, were examined for their capacity of inducing release of microglial superoxide. The neurotoxicity of these peptides was measured according to their influence on the ability of neuroglial cultures deficient in gp91 (phox) , the catalytic unit of NADPH oxidase (Nox2), or wild-type cultures to take up (3)H-labeled dopamine and on the number of tyrosine hydroxylase-staining-positive neurons. Western blots and confocal images were utilized to analyze membrane translocation of p47 (phox) and p67 (phox) , phosphorylation of p47 (phox) and Erk1/2 kinase, and binding of α-Syn peptides to gp91 (phox) . Activation of brain microglia in mice injected with α-Syn peptides was demonstrated by immunostaining for major histocompatibility complex (MHC)-II along with qPCR for Iba-1 and MHC-II.

resultsWe report α-Syn (29-40) as a specific peptide capable of activating microglial Nox2 to produce superoxide and cause dopaminergic neuronal damage. Administered to mice, this peptide also activated brain microglia to increase expression of MHC-II and Iba-1 and stimulated oxidation reaction. Exploring the underlying mechanisms showed that α-Syn (29-40) peptide triggered Nox2 to generate extracellular superoxide and its metabolite H2O2 by binding to the catalytic unit gp91 (phox) of Nox2; diffusing into cytosol, H2O2 activated Erk1/2 kinase to phosphorylate p47 (phox) and p67 (phox) and further activated Nox2, establishing a positive feedback loop to amplify the Nox2-mediated response.

conclusionsCollectively, our study suggests novel information regarding how α-Syn causes neuronal injury, possibly including mechanisms involving abnormal metabolites of α-Syn aggregates.

Indexed as

alpha-SynucleinAnimalsAnimals, NewbornCalcium-Binding ProteinsCells, CulturedDisease Models, AnimalDopaminergic NeuronsEmbryo, MammalianHistocompatibility Antigens Class IIMAP Kinase Signaling SystemMembrane GlycoproteinsMiceMice, Inbred C57BLMice, KnockoutMicrofilament ProteinsNADPH Oxidase 2Aif1 protein, mousealpha-SynucleinCalcium-Binding ProteinsCybb protein, mouseHistocompatibility Antigens Class IIMembrane GlycoproteinsMicrofilament ProteinsNADPH Oxidase 2NADPH OxidasesPeptide FragmentsPirb protein, mouseReceptors, ImmunologicSuperoxidesTyrosine 3-Monooxygenasegp91 phoxMicrogliaNeuronal damageSuperoxideα-Synuclein

Identifiers

PMID27329107
PMCPMC4915166
OpenAlexW2463222011

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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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.