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The harlequin mouse mutation downregulates apoptosis-inducing factor

Author

Listed:
  • Jeffrey A. Klein

    (The Jackson Laboratory)

  • Chantal M. Longo-Guess

    (The Jackson Laboratory)

  • Marlies P. Rossmann

    (The Jackson Laboratory)

  • Kevin L. Seburn

    (The Jackson Laboratory)

  • Ronald E. Hurd

    (The Jackson Laboratory)

  • Wayne N. Frankel

    (The Jackson Laboratory)

  • Roderick T. Bronson

    (The Jackson Laboratory
    Tufts University School of Veterinary Medicine)

  • Susan L. Ackerman

    (The Jackson Laboratory)

Abstract

Harlequin (Hq) mutant mice have progressive degeneration of terminally differentiated cerebellar and retinal neurons. We have identified the Hq mutation as a proviral insertion in the apoptosis-inducing factor (Aif) gene, causing about an 80% reduction in AIF expression. Mutant cerebellar granule cells are susceptible to exogenous and endogenous peroxide-mediated apoptosis, but can be rescued by AIF expression. Overexpression of AIF in wild-type granule cells further decreases peroxide-mediated cell death, suggesting that AIF serves as a free radical scavenger. In agreement, dying neurons in aged Hq mutant mice show oxidative stress. In addition, neurons damaged by oxidative stress in both the cerebellum and retina of Hq mutant mice re-enter the cell cycle before undergoing apoptosis. Our results provide a genetic model of oxidative stress-mediated neurodegeneration and demonstrate a direct connection between cell cycle re-entry and oxidative stress in the ageing central nervous system.

Suggested Citation

  • Jeffrey A. Klein & Chantal M. Longo-Guess & Marlies P. Rossmann & Kevin L. Seburn & Ronald E. Hurd & Wayne N. Frankel & Roderick T. Bronson & Susan L. Ackerman, 2002. "The harlequin mouse mutation downregulates apoptosis-inducing factor," Nature, Nature, vol. 419(6905), pages 367-374, September.
    • Handle: RePEc:nat:nature:v:419:y:2002:i:6905:d:10.1038_nature01034
    DOI: 10.1038/nature01034
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    Cited by:

    1. Declan Timothy Waugh, 2019. "The Contribution of Fluoride to the Pathogenesis of Eye Diseases: Molecular Mechanisms and Implications for Public Health," IJERPH, MDPI, vol. 16(5), pages 1-28, March.
    2. Xuemeng Zhou & Tsz Wing Sam & Ah Young Lee & Danny Leung, 2021. "Mouse strain-specific polymorphic provirus functions as cis-regulatory element leading to epigenomic and transcriptomic variations," Nature Communications, Nature, vol. 12(1), pages 1-18, December.

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