Evidence map›Paper›PMID 25497688›Full record

ArticleNeurobiology of disease2015

Overexpression of alpha-synuclein at non-toxic levels increases dopaminergic cell death induced by copper exposure via modulation of protein degradation pathways.

Annadurai Anandhan, Humberto Rodriguez-Rocha, Iryna Bohovych, Amy M Griggs, Laura Zavala-Flores, Elsa M Reyes-Reyes, Javier Seravalli, Lia A Stanciu, Jaekwon Lee, Jean-Christophe Rochet and 2 more

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

Article in Neurobiology of disease, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
37citing papers in PubMed, 1 pooled it
4.9field-weighted citation impact, top 5% 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

37 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.

  1. Pooled it
  2. Review
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  4. Article
  5. Review
  6. Environmental toxins in neurodegeneration - a narrative review.Neurological research and practice · 2025
    Review
  7. Review
  8. Cuproptosis: Mechanism and Application in Lymphoma.Current cancer drug targets · 2025
    Review
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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

12 authors at 3 institutions in 1 country.

Annadurai AnandhanRedox Biology Center, University of Nebraska-Lincoln, Lincoln, NE, USA; School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, USA.
Humberto Rodriguez-RochaRedox Biology Center, University of Nebraska-Lincoln, Lincoln, NE, USA; School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, USA.
Iryna BohovychDepartment of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, USA.
Amy M GriggsDepartment of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
Laura Zavala-FloresRedox Biology Center, University of Nebraska-Lincoln, Lincoln, NE, USA; School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, USA.
Elsa M Reyes-ReyesCollege of Medicine, The University of Arizona, Tucson, AZ, USA.
Javier SeravalliRedox Biology Center, University of Nebraska-Lincoln, Lincoln, NE, USA; Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, USA.
Lia A StanciuWeldon School of Biomedical Engineering and School of Materials Engineering, Purdue University, West Lafayette, IN, USA.
Jaekwon LeeRedox Biology Center, University of Nebraska-Lincoln, Lincoln, NE, USA; Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, USA.
Jean-Christophe RochetDepartment of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
Oleh KhalimonchukRedox Biology Center, University of Nebraska-Lincoln, Lincoln, NE, USA; Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, USA.
Rodrigo FrancoRedox Biology Center, University of Nebraska-Lincoln, Lincoln, NE, USA; School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, USA. Electronic address: rfrancocruz2@unl.edu.
University of Nebraska–Lincoln · USPurdue University West Lafayette · USUniversity of Arizona · US

Funding

THE REDOX-MEDIATED REGULATION OF IRON-RESPONSIVE GENE EXPRESSION IN LIVERP20RR017675 · NCRR · UNIVERSITY OF NEBRASKA LINCOLN · PI BIDASEE, KESHORE R · 2002 to 2011
$20.4M
Redox Biology CenterP30GM103335 · NIGMS · UNIVERSITY OF NEBRASKA LINCOLN · PI BECKER, DONALD F · 2012 to 2016
$4.3M
Nebraska Center for VirologyP30GM103509 · NIGMS · UNIVERSITY OF NEBRASKA LINCOLN · PI WOOD, CHARLES · 2012 to 2014
$3.3M
A Conserved Metalloprotease Required for Mitochondrial Maintenance and ProtectionR01GM108975 · NIGMS · UNIVERSITY OF NEBRASKA LINCOLN · PI KHALIMONCHUK, OLEH · 2014 to 2018
$1.4M
Mechanistic insights into cellular metal detoxificationR01ES016337 · NIEHS · UNIVERSITY OF NEBRASKA LINCOLN · PI LEE, JAEKWON · 2009 to 2013
$1.4M
Membrane binding and aggregation of alpha-synucleinR01NS049221 · NINDS · PURDUE UNIVERSITY · PI ROCHET, JEAN-CHRISTOPHE · 2006 to 2009
$960k
Metal-Induced Structural Transformations during Alpha-Synuclein Aggregation.K25NS058395 · NINDS · PURDUE UNIVERSITY · PI STANCIU, LIA · 2008 to 2012
$814k
NCRR NIH HHS P20 RR017675NCRR NIH HHS P20RR17675NIEHS NIH HHS ES016337NIEHS NIH HHS R01 ES016337NIGMS NIH HHS GM108975NIGMS NIH HHS P30 GM103335NIGMS NIH HHS P30 GM103509NIGMS NIH HHS R01 GM108975NINDS NIH HHS NS049221NINDS NIH HHS NS058395-04
6 · The paper itself

Abstract

Gene multiplications or point mutations in alpha (α)-synuclein are associated with familial and sporadic Parkinson's disease (PD). An increase in copper (Cu) levels has been reported in the cerebrospinal fluid and blood of PD patients, while occupational exposure to Cu has been suggested to augment the risk to develop PD. We aimed to elucidate the mechanisms by which α-synuclein and Cu regulate dopaminergic cell death. Short-term overexpression of wild type (WT) or mutant A53T α-synuclein had no toxic effect in human dopaminergic cells and primary midbrain cultures, but it exerted a synergistic effect on Cu-induced cell death. Cell death induced by Cu was potentiated by overexpression of the Cu transporter protein 1 (Ctr1) and depletion of intracellular glutathione (GSH) indicating that the toxic effects of Cu are linked to alterations in its intracellular homeostasis. Using the redox sensor roGFP, we demonstrated that Cu-induced oxidative stress was primarily localized in the cytosol and not in the mitochondria. However, α-synuclein overexpression had no effect on Cu-induced oxidative stress. WT or A53T α-synuclein overexpression exacerbated Cu toxicity in dopaminergic and yeast cells in the absence of α-synuclein aggregation. Cu increased autophagic flux and protein ubiquitination. Impairment of autophagy by overexpression of a dominant negative Atg5 form or inhibition of the ubiquitin/proteasome system (UPS) with MG132 enhanced Cu-induced cell death. However, only inhibition of the UPS stimulated the synergistic toxic effects of Cu and α-synuclein overexpression. Our results demonstrate that α-synuclein stimulates Cu toxicity in dopaminergic cells independent from its aggregation via modulation of protein degradation pathways.

Indexed as

alpha-SynucleinAnimalsApoptosisCaspasesCells, CulturedCopperCysteine Proteinase InhibitorsDopaminergic NeuronsEmbryo, MammalianGene Expression RegulationHumansLeupeptinsMesencephalonMutationNeuroblastomaProteolysisalpha-Synucleinbenzyloxycarbonylleucyl-leucyl-leucine aldehydeCaspasesCoppercupric chlorideCysteine Proteinase InhibitorsLeupeptinsTyrosine 3-MonooxygenaseA53TAMPKAutophagyCopper and Parkinson's diseaseOxidative stressProteasomeUbiquitinationα-Synuclein

Identifiers

PMID25497688
PMCPMC4459946
OpenAlexW2077043544

What OpenQuestion holds

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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.