Modeling SCA8 Pathogenesis in the

Mutsuddi et al. (2004) have developed a Drosophila model of SCA8. These investigators have shown that expression of SCA8 transcripts with both the normal and the expanded repeat tracts in the Drosophila retina induces a late-onset, progressive neurodegeneration. Using this neurodegenerative pheno-type as a sensitized background for a genetic modifier screen, this group performed a targeted screen of a panel of available mutants in RNA binding proteins to look for dominant modifiers of the SCA8 phenotype. Three enhancer mutations in muscleblind, split ends, and staufen and one suppressor mutation in CG3249, which encodes a putative protein kinase A anchor protein (PKAAP) with a K-homology-type RNA binding motif, were identified. All four of these genes encode neuronally expressed RNA binding proteins that are conserved in Drosophila and humans. Although expression of both normal and expanded repeat tracts causes neurodegeneration in this model, the interaction between muscleblind and SCA8 varies in relation to d(CTG) repeat size. These experiments suggest that the SCA8 expansion can alter interactions with RNA binding proteins, which could in turn play a role in disease pathogenesis (Mutsuddi et al. 2004).

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