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Nature 419, 367-374 (26 September 2002) | doi:10.1038/nature01034; Received 23 May 2002; Accepted 26 July 2002

The harlequin mouse mutation downregulates apoptosis-inducing factor

Jeffrey A. Klein1, Chantal M. Longo-Guess1, Marlies P. Rossmann1, Kevin L. Seburn1, Ronald E. Hurd1, Wayne N. Frankel1, Roderick T. Bronson1,2 & Susan L. Ackerman1

  1. The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA
  2. Tufts University School of Veterinary Medicine, 200 Westboro Road, North Grafton, Massachusetts 01536, USA

Correspondence to: Susan L. Ackerman1 Correspondence and requests for materials should be addressed to S.L.A. (e-mail: Email: sla@jax.org).

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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.