Characterization of Drosophila and human atrophin using Drosophila model system

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant progressive neurodegenerative disease caused by the expansion of polyglutamine repeats (poly-Q) within the Atrophin-1 protein. The in vivo function of Atrophin-1 is not well understood. We have previously characterized a Drosophila gene encoding an Atrophin family protein, Drosophila Atrophin (dAtr), which functions as a versatile transcription corepressor. In the present study, I show that human Atrophin-1, like its Drosophila counterpart, represses transcription in vivo when it binds to target DNA, and poly-Q expansion in human Atrophin-I reduces this repressive activity. Over expression of poly-Q expanded human Atrophin-1 in fly eyes causes progressive neurodegeneration. The action of dAtr was studied using microarray gene expression profiling of dAtr in adult flies. Flies with endogenous Atrophin level acutely knocked down were compared with flies acutely overexpressing dAtr, polyglutamine-expanded dAtr (dAtrQ112) or flies expressing a polyglutamine tract only (poly-Q75).; We find that a significant portion of those genes affected by dAtr overexpression were affected also, in the opposite direction, by dAtr knockdown. Polyglutamine expansion in dAtr greatly alters normal transcriptional regulation and gains novel regulatory function of dAtr. About 30% of genes whose expression level were changed in dAtrQ112 are also affected in that of poly-Q 75. This indicates that expanded polyglutamine itself has a significant effect on the gene expression. This is further supported by the result from DamID and genomic DNA tiling path microarray experiments as poly-Q 75 directly binds DNA.