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Cited by 62Redox biology and oxidative stressNeurogenesis and neuroplasticity mechanismsDevelopmental Biology and Gene Regulation

Prdx4 is a compartment-specific H2O2 sensor that regulates neurogenesis by controlling surface expression of GDE2

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Yan, Ye, Wladyka, Cynthia, Fujii, Junichi, Sockanathan, Shanthini·2015·Nature Communications
DOI 10.1038/ncomms8006PMC PMC4432624
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Abstract

Neural progenitors and terminally differentiated neurons show distinct redox profiles, suggesting that coupled-redox cascades regulate the initiation and progression of neuronal differentiation. Discrete cellular compartments have different redox environments and how they contribute to differentiation is unclear. Here we show that Prdx4, an endoplasmic reticulum (ER) enzyme that metabolizes H 2 O 2, acts as a tunable regulator of neurogenesis via its compartmentalized thiol-oxidative function. Prdx4 ablation causes premature motor neuron differentiation and progenitor depletion, leading to imbalances in subtype-specific motor neurons. GDE2, a six-transmembrane protein that induces differentiation by downregulating Notch signalling through surface cleavage of GPI-anchored proteins, is targeted by Prdx4 oxidative activity. Prdx4 dimers generated by H 2 O 2 metabolism oxidize two cysteine residues within the GDE2 enzymatic domain, which blocks GDE2 trafficking to the plasma membrane and prevents GDE2 neurogeneic function. Thus, Prdx4 oxidative activity acts as a sensor to directly couple neuronal differentiation with redox environments in the ER.

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  • PRDX4 thiol oxidation of GDE2 in the ER-trans Golgi network prevents trafficking of mature GDE2 to the plasma membrane and leads to GDE2 intracellular sequestration.

    “In contrast, PRDX4 thiol oxidation of GDE2 in the ER-trans Golgi network prevents trafficking of mature GDE2 to the plasma membrane and leads to GDE2 intracellular sequestration (46).”

    From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [46]

    The Results (‘Prdx4 inhibits GDE2 through thiol oxidation’ and ‘Prdx4 inhibits GDE2 surface trafficking’; page unavailable) support GDE2 thiol oxidation and reduced surface expression in the presence of Prdx4. The Discussion places the proposed inhibition of trafficking within the ER, not the ER–trans-Golgi network; the cited passages also do not establish that the sequestered GDE2 is mature. (LLM, conf=0.88)

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Cited by

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Authors
Yan, Y., Wladyka, C., Fujii, J., & Sockanathan, S.
Affiliations
  • Johns Hopkins University (US)
  • Yamagata University (JP)
Corresponding author
Sockanathan, Shanthini
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2015-05-06
Volume
6
Issue
1
Pages
7006-7006
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms8006
PMC
PMC4432624
OpenAlex
W2253740283
Cited by
62
References
2
Citations by year
2026: 6 · 2025: 4 · 2024: 4 · 2023: 2 · 2022: 1 · 2021: 14 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 7 · 2016: 7 · 2015: 1
FWCI
2.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Muscular Dystrophy Association
  • National Institute of Neurological Disorders and Stroke (R01NS046336)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
peroxiredoxin 4, hydrogen peroxide, redox signaling, neurogenesis, motor neuron differentiation, neural progenitor cells, endoplasmic reticulum, Notch signaling, GPI-anchored proteins, protein trafficking, cysteine oxidation
MeSH terms
Amino Acid Sequence, Animals, Cell Compartmentation, Cell Cycle, Cell Differentiation, Cell Membrane, Chickens, Cysteine, Epistasis, Genetic, Hydrogen Peroxide, Molecular Sequence Data, Motor Neurons, Oxidation-Reduction, Phosphoric Diester Hydrolases, Protein Binding, Spinal Cord, Sulfhydryl Compounds, Mice, Peroxiredoxins, Neurogenesis

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