Abstract 1299 A balancing act: Pan-neuronal over-expression of ataxin1 in Drosophila melanogaster leads to decreased life span and subtle behavioral deficits

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a translated CAG repeat encoding glutamine in the ataxin-1 (Atx-1) protein. Interestingly, while overexpression of mutant Atx-1 with an expanded polyQ tract causes neurodegeneration in mice and flies, even human Atx-1 with a nonpathogenic repeat of (CAG)14CAT-CAG-CAT(CAG)15, such as hAtx-1[30Q], causes neuronal degeneration if expressed at sufficiently high levels in either mice or Drosophila. To understand the physiological consequences of overexpression of Atx-1 in flies, the yeast two hybrid system was employed where wild-type ataxin-1 under UAS was driven pan-neuronally in nervous tissue of Drosophila melanogaster using the elav-GAL4 driver (elav-GAL4/UAS-Atx-1). Parallel controls were UAS-ATX-1/+ and elav-GAL4/+. The lifespan of flies overexpressing Atx-1 was significantly reduced compared to controls. While daily locomotor activity rhythms were not markedly affected, the negative geotaxis response was significantly impacted in flies overexpressing Atx-1. The expression of armadillo which is required for both for cell–cell adhesion and for regulating gene expression during development was markedly reduced. Moreover, Drosophila Nemo (nmo) a member of a conserved family of protein kinases that have roles in diverse signaling processes during development was also affected. Taken together, our results point to a specific level of ataxin necessary for proper development and enhanced levels can have physiologically detrimental effects.