Evidence map›Paper›PMID 33637689›Full record

ArticleCell death & disease2021

Targeted de-repression of neuronal Nrf2 inhibits α-synuclein accumulation.

Paul S Baxter, Nóra M Márkus, Owen Dando, Xin He, Bashayer R Al-Mubarak, Jing Qiu, Giles E Hardingham

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

Article in Cell death & disease, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.

0numbers the graph read from it
0cells of the map it votes in
17citing papers in PubMed
1.4field-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

17 citing papers in PubMed, 25 citations in OpenAlex.

  1. Article
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  3. Nrf2 signaling pathway and its molecular regulatory mechanism.Journal of Zhejiang University. Science. B · 2026
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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

7 authors at 2 institutions in 1 country.

Paul S BaxterUK Dementia Research Institute at the University of Edinburgh, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK. Paul.Baxter@ed.ac.uk.
Nóra M MárkusUK Dementia Research Institute at the University of Edinburgh, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK.
Owen DandoUK Dementia Research Institute at the University of Edinburgh, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK.
Xin HeUK Dementia Research Institute at the University of Edinburgh, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK.
Bashayer R Al-MubarakUK Dementia Research Institute at the University of Edinburgh, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK.
Jing QiuUK Dementia Research Institute at the University of Edinburgh, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK.
Giles E HardinghamUK Dementia Research Institute at the University of Edinburgh, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK. Giles.Hardingham@ed.ac.uk.ORCID 0000-0002-7629-5314
UK Dementia Research Institute · GBMedical Research Scotland · GB

Funding

Medical Research Council
6 · The paper itself

Abstract

Many neurodegenerative diseases are associated with neuronal misfolded protein accumulation, indicating a need for proteostasis-promoting strategies. Here we show that de-repressing the transcription factor Nrf2, epigenetically shut-off in early neuronal development, can prevent protein aggregate accumulation. Using a paradigm of α-synuclein accumulation and clearance, we find that the classical electrophilic Nrf2 activator tBHQ promotes endogenous Nrf2-dependent α-synuclein clearance in astrocytes, but not cortical neurons, which mount no Nrf2-dependent transcriptional response. Moreover, due to neuronal Nrf2 shut-off and consequent weak antioxidant defences, electrophilic tBHQ actually induces oxidative neurotoxicity, via Nrf2-independent Jun induction. However, we find that epigenetic de-repression of neuronal Nrf2 enables them to respond to Nrf2 activators to drive α-synuclein clearance. Moreover, activation of neuronal Nrf2 expression using gRNA-targeted dCas9-based transcriptional activation complexes is sufficient to trigger Nrf2-dependent α-synuclein clearance. Thus, targeting reversal of the developmental shut-off of Nrf2 in forebrain neurons may alter neurodegenerative disease trajectory by boosting proteostasis.

Indexed as

CRISPR-Cas SystemsGene Targetingalpha-SynucleinAnimalsAstrocytesCell DeathCells, CulturedClustered Regularly Interspaced Short Palindromic RepeatsCoculture TechniquesCRISPR-Associated Protein 9Epigenetic RepressionFemaleHydroquinonesLewy Body DiseaseMaleMice2-tert-butylhydroquinonealpha-SynucleinCRISPR-Associated Protein 9HydroquinonesNeuroprotective AgentsNfe2l2 protein, mouseNF-E2-Related Factor 2SNCA protein, human

Identifiers

PMID33637689
PMCPMC7910424
OpenAlexW3132886803

What OpenQuestion holds

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LicenceCC BY
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.