Genetic and biochemical analysis of the Drosophila melanogaster homolog of the human SCA2 gene
Satterfield, Terrence Forrest
MetadataShow full item record
The polyglutamine repeat diseases are a group of dominantly inherited neurodegenerative disorders characterized by progressive degeneration of specific neuronal populations and a shared mutational mechanism involving expansion of a glutamine-encoding repeat in the corresponding genes. Work on several polyglutamine diseases has led to the finding that nuclear localization of long polyglutamine tracts can trigger neurodegeneration via mechanisms involving transcriptional interference. While transcriptional interference may account for pathology in some of the polyglutamine disorders, increasing evidence indicates that unique nuclear and non-nuclear pathways are involved in the different polyglutamine disorders.An alternative model to explain pathology in the polyglutamine repeat disorders is that pathogenesis results from an alteration of the normal cellular function of the polyglutamine disease gene as a consequence of polyglutamine expansion. Although data support this hypothesis for several polyglutamine repeat disorders, this model has not been broadly tested, in part because the normal cellular functions of most polyglutamine disease genes remain unknown.This dissertation focuses on studies involving SCA2, the human gene underlying the polyglutamine disease spinocerebellar ataxia type 2 (SCA2). To understand the mechanism of SCA2 pathogenesis, I have used the fruit fly Drosophila melanogaster as a model system to investigate the normal cellular function of a SCA2 homolog (Datx2). I have shown that, like its human counterpart, Datx2 encodes a cytoplasmic protein present throughout development in a variety of tissue types, including the nervous system. Loss of Datx2 function in the retina, sensory bristles, and female germline results in cellular and tissue morphological changes indicative of actin filament formation defects. Moreover, loss-of-function or overexpression of Datx2 in these same tissues results in alterations in the structural characteristics of actin filaments. Biochemical analysis of Datx2 and ataxin-2 (encoded by SCA2) reveal that both proteins physically assemble with polyribosomes, thus indicating that these proteins function in cytoplasmic RNA metabolism. These results suggest that SCA2/Datx2 function to regulate RNAs encoding components of actin filament formation pathways. Further, these results raise the possibility that polyglutamine induced alteration of SCA2 function causes dysregulation of the actin cytoskeleton, resulting in the neural pathology observed in SCA2.
- Genetics