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As harlequins grow old

The gene underlying underlying progressive neurodegeneration in the harlequin mouse mutant is a mitochondrial oxidorectase involved in cell death.

Jonathan Weitzman(jonathanweitzman@hotmail.com)

The harlequin (Hq) mouse mutant serves as a model for late-onset neurodegenerative disease. In the September 26 Nature, Jeffery Klein and colleagues define the genetic basis of the Hq mutant and provide a molecular link between free-radical damage, oxidative stress and neuronal cell death (Nature, 419:367-374, September 26, 2002).

Klein et al. show that the Hq phenotype is linked to progressive neuronal apoptosis in the cerebellum and late-onset retinal degeneration. Genetic analysis revealed the presence of an ecotropic proviral insertion within rhe first intron of the gene encoding apoptosis-inducing factor (AIF) that results in a dramatic reduction in expression. AIF is a mitochondrial oxidoreductase that can translocate to the nucleus and induce cell death. They show that loss of AIF leads to oxidative stress and increased levels of catalase and glutathione. The granule cells from Hq mutant animals were sensitive to peroxides, and this sensitivity...

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