The harlequin mouse mutation downregulates apoptosis-inducing factor

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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.

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Figure 1: Progressive ataxia in Hq mutant mice is correlated with the loss of cerebellar granule and Purkinje cells.
Figure 2: Progressive retinal degeneration in Hq mutant mice.
Figure 3: The Hq mutation is an ecotropic proviral insertion in the Aif gene.
Figure 4: Oxidative-stress-associated responses in Hq mutant mice.
Figure 5: AIF- and peroxide/non-peroxide-mediated cell death in primary neuronal cultures.
Figure 6: Oxidatively damaged neurons re-enter the cell cycle in Hq mutant mice.


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We thank C. Mathews for providing antioxidant antibodies; R. Smith and L. Dionne for technical assistance; J. Stockwell for statistical assistance; L. Bechtold and P. Finger for electron microscopy work; G. Martin and J. Smith for assistance with the images; and T. Gridley, E. Leiter, B. Knowles and P. Nishina for comments on the manuscript. This work was supported by NIH grants to S.L.A., a NIH training grant to J.A.K. and an institutional NCI cancer core grant.

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Correspondence to Susan L. Ackerman.

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Klein, J., Longo-Guess, C., Rossmann, M. et al. The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature 419, 367–374 (2002) doi:10.1038/nature01034

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