The function of Luan, a Drosophila homolog of human atrophin-1 in neurodegeneration and development

Atrophin-1 is the causative gene for Dentatorubral-pallidoluysian atrophy (DRPLA), which belongs to a family of progressive neurodegenerative diseases caused by expansion of glutamine repeats within the disease responsible proteins. The biological function of Atrophin-1 and the pathogenic mechanism underlying neurodegeneration were unknown. In a mosaic screen using the FRT/flipase recombination system, I isolated mutations in the Drosophila homolog of Atrophin-1 gene which we named as luan.; My research uncovered the normal in vivo function of luan. Analysis of the Luan expression pattern shows that Luan is a nuclear protein expressed ubiquitously throughout development. Characterization of luau mutant phenotypes indicates Luan's activity is required in multiple signaling pathways during development, including the Frizzled/Wnt signaling cascade. During embryogenesis, luan regulates neurogenesis, segmentation and dorsoventral patterning. Detailed analysis of segmentation defects in luan mutants suggests Luan is involved in transcriptional regulation. Further analysis demonstrates Luan functions as a transcriptional co-repressor of even-skipped (eve). Maternally contributed luan genetically interacts with the transcription repressors eve and huckebein (hkb ). Luan binds to both Eve and Hkb in vitro and mediates Eve's repressive activity in vivo. These results define luan functions as a versatile transcriptional co-repressor, which further suggests that deregulation of gene expression contributes to the pathogenic mechanism of progressive neurodegeneration. This work is the first to assign a biological function to a Atrophin-1 family protein and represents an important contribution to our understanding of polyglutamine diseases.; My research also established a polyglutamine disease model in Drosophila. Transgenic flies carrying full-length Luan with expanded glutamine repeats were generated. Overexpression of the mutant form of Luan causes a neurodegenerative phenotype in the Drosophila eye. Further studies reveal that expansion of glutamine repeats confers a dominant toxic effect on the host protein. Furthermore, the induced degeneration process is not correlated with cell apoptosis or the formation of nuclear inclusions. The results also demonstrate that expansion of glutamine repeats does not abolish Luan's normal function, or alter its cellular distribution pattern. This Drosophila polyglutamine disease model will facilitate the uncovering of other genetic factors involved in the initiation and progression of neurodegeneration.