Evidence map›Paper›PMID 25863526›Full record

ArticleNeurobiology of aging2015

The loss of glucose-regulated protein 78 (GRP78) during normal aging or from siRNA knockdown augments human alpha-synuclein (α-syn) toxicity to rat nigral neurons.

Maxim Salganik, Valeriy G Sergeyev, Vishal Shinde, Craig A Meyers, Marina S Gorbatyuk, Jonathan H Lin, Sergey Zolotukhin, Oleg S Gorbatyuk

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neurobiology of aging, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.

0numbers the graph read from it
0cells of the map it votes in
42citing papers in PubMed
–field-weighted citation impact
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

42 citing papers in PubMed.

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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

8 authors.

Maxim SalganikDepartment of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA; The Powell Gene Therapy Center, College of Medicine, University of Florida, Gainesville, FL, USA; Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Valeriy G SergeyevDepartment of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Biology, Udmurt State University, Izhevsk, Russia.
Vishal ShindeDepartment of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
Craig A MeyersDepartment of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA.
Marina S GorbatyukDepartment of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
Jonathan H LinDepartment of Pathology, University of California, La Jolla, CA, USA.
Sergey ZolotukhinThe Powell Gene Therapy Center, College of Medicine, University of Florida, Gainesville, FL, USA; Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.
Oleg S GorbatyukDepartment of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Neurology, Center for Neurodegeneration and Experimental Therapy, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: oleggor@uab.edu.

Funding

Visual Phenotyping CoreP30EY003039 · NEI · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI J CRAWFORD DOWNS · 1985 to 2026
$16.9M
Endoplasmic Reticulum Stress in Retinal DegenerationR01EY020846 · NEI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI LIN, JONATHAN · 2010 to 2014
$1.9M
Unfolded Protein Response as a Therapeutic Target for ADRP Animal ModelsR01EY020905 · NEI · UNIVERSITY OF NORTH TEXAS HLTH SCI CTR · PI GORBATYUK, MARINA · 2010 to 2014
$1.3M
Cellular and Molecular Mechanisms of Age-Related Retinal DegenerationI01BX002284 · VA · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · PI LIN, JONATHAN · 2014 to 2023
–
BLRD VA I01 BX002284NEI NIH HHS P30 EY003039NEI NIH HHS R01 EY020846NEI NIH HHS R01EY020846NEI NIH HHS R01 EY020905NEI NIH HHS R01EY020905
6 · The paper itself

Abstract

Age-related structural changes and gradual loss of key enzymes significantly affect the ability of the endoplasmic reticulum (ER) to facilitate proper protein folding and maintain homeostasis. In this work, we present several lines of evidence supporting the hypothesis that the age-related decline in expression of the ER chaperone glucose-regulated protein 78 (GRP78) could be related to the development of Parkinson's disease. We first determined that old (24 months) rats exhibit significantly lower levels of GRP78 protein in the nigrostriatal system as compared with young (2 months) animals. Then using recombinant adeno-associate virus-mediated gene transfer, we found that GRP78 downregulation by specific small interfering RNAs (siRNAs) aggravates alpha-synuclein (α-syn) neurotoxicity in nigral dopamine (DA) neurons. Moreover, the degree of chaperone decline corresponds with the severity of neurodegeneration. Additionally, comparative analysis of nigral tissues obtained from old and young rats revealed that aging affects the capacity of nigral DA cells to upregulate endogenous GRP78 protein in response to human α-syn neurotoxicity. Finally, we demonstrated that a sustained increase of GRP78 protein over the course of 9 months protected aging nigral DA neurons in the α-syn-induced rat model of Parkinson's-like neurodegeneration. Our data indicate that the ER chaperone GRP78 may have therapeutic potential for preventing and/or slowing age-related neurodegeneration.

Indexed as

Gene Knockdown TechniquesHeat-Shock ProteinsRNA, Small InterferingAgingalpha-SynucleinAnimalsDisease Models, AnimalDopaminergic NeuronsDown-RegulationEndoplasmic ReticulumEndoplasmic Reticulum Chaperone BiPFemaleHomeostasisHumansMaleMolecular Chaperonesalpha-SynucleinEndoplasmic Reticulum Chaperone BiPGRP78 protein, ratHeat-Shock ProteinsHSPA5 protein, humanMolecular ChaperonesRNA, Small InterferingDopamineGlucose regulated protein 78Parkinson DiseaseRecombinant Adeno-associated virusSubstantia nigra pars compactaTyrosine hydroxylase

Identifiers

PMID25863526
PMCPMC4433578

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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.