Evidence map›Paper›PMID 33242767›Full record

ArticleRedox biology2020

Reductive stress promotes protein aggregation and impairs neurogenesis.

Kishore Kumar S Narasimhan, Asokan Devarajan, Goutam Karan, Sandhya Sundaram, Qin Wang, Thomas van Groen, Federica Del Monte, Namakkal S Rajasekaran

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

Article in Redox biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.

0numbers the graph read from it
0cells of the map it votes in
21citing papers in PubMed
1.9field-weighted citation impact, top 13% 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

21 citing papers in PubMed, 41 citations in OpenAlex.

  1. Article
  2. Article
  3. Nanomedicine-Driven Modulation of Reductive Stress for Cancer Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025
    Review
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  6. Nrf2/Bach1 signaling axis: A promising multifaceted therapeutic strategy for Alzheimer's disease.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025
    Review
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  9. The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2023
    Article
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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 at 5 institutions in 2 countries.

Kishore Kumar S NarasimhanCardiac Aging & Redox Signaling Laboratory, Molecular and Cellular Pathology, Department of Pathology, Birmingham, AL, USA.
Asokan DevarajanDepartment of Medicine, Division of Cardiology, Cardiac Arrhythmia Center and Neurocardiology Research Center of Excellence, University of California, Los Angeles, CA, United States.
Goutam KaranDepartment of Human Genetics, University of Utah, Salt Lake City, UT, USA.
Sandhya SundaramDepartment of Pathology, Sri Ramachandra Medical University & Research Institute, Chennai, India.
Qin WangDepartment of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
Thomas van GroenDepartment of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
Federica Del MonteGazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
Namakkal S RajasekaranCardiac Aging & Redox Signaling Laboratory, Molecular and Cellular Pathology, Department of Pathology, Birmingham, AL, USA; Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: rajnsr@uabmc.edu.
University of Alabama at Birmingham · USMedical University of South Carolina · USSri Ramachandra Institute of Higher Education and Research · INUniversity of California, Los Angeles · USUniversity of Utah · US

Funding

Reductive Stress Induces Proteotoxic Cardiac DiseaseR01HL118067 · NHLBI · UNIVERSITY OF UTAH · PI NAMAKKAL SOORAPPAN, RAJASEKARAN · 2013 to 2021
$4.5M
Antioxidant Defense Mechanisms: Nrf2/Keap1 Signaling in Aging HeartR03AG042860 · NIA · UNIVERSITY OF UTAH · PI NAMAKKAL SOORAPPAN, RAJASEKARAN · 2012 to 2013
$145k
NHLBI NIH HHS R01 HL118067NIA NIH HHS R03 AG042860
6 · The paper itself

Abstract

Redox homeostasis regulates key cellular signaling in both physiology and pathology. While perturbations result in shifting the redox homeostasis towards oxidative stress are well documented, the influence of reductive stress (RS) in neurodegenerative diseases and its mechanisms are unknown. Here, we postulate that a redox shift towards the reductive arm (through the activation of Nrf2 signaling) will damage neurons and impair neurogenesis. In proliferating and differentiating neuroblastoma (Neuro 2a/N2a) cells, sulforaphane-mediated Nrf2 activation resulted in increased transcription/translation of antioxidants and glutathione (GSH) production along with significantly declined ROS in a dose-dependent manner leading to a reductive-redox state (i.e. RS). Interestingly, this resulted in endoplasmic reticulum (ER) stress leading to subsequent protein aggregation/proteotoxicity in neuroblastoma cells. Under RS, we also observed elevated Tau/α-synuclein and their co-localization with other protein aggregates in these cells. Surprisingly, we noticed that acute RS impaired neurogenesis as evidenced from reduced neurite outgrowth/length. Furthermore, maintaining the cells in a sustained RS condition (for five consecutive generations) dramatically reduced their differentiation and prevented the formation of axons (p < 0.05). This impairment in RS mediated neurogenesis occurs through the alteration of Tau dynamics i.e. RS activates the pathogenic GSK3β/Tau cascade thereby promoting the phosphorylation of Tau leading to proteotoxicity. Of note, intermittent withdrawal of sulforaphane from these cells suppressed the proteotoxic insult and re-activated the differentiation process. Overall, this results suggest that either acute or chronic RS could hamper neurogenesis through GSK3β/TAU signaling and proteotoxicity. Therefore, investigations identifying novel redox mechanisms impacting proteostasis are crucial to preserve neuronal health.

Indexed as

Oxidative StressProtein AggregatesEndoplasmic Reticulum StressNeurogenesisOxidation-ReductionProtein AggregatesER stressGlutathioneNeurogenesisNrf2ProteotoxicityReductive stress

Identifiers

PMID33242767
PMCPMC7695986
OpenAlexW3089804290

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
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.