Drosophila Melanogaster

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A genetic model for human polyglutamine-repeat disease in Drosophila melanogaster
Nancy M. Bonini Phil. Trans. R. Soc. Lond. B 1999 354, 1057-1060 doi: 10.1098/rstb.1999.0458

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A genetic model for human polyglutaminerepeat disease in Drosophila melanogaster
Nancy M. Bonini
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104- 6018, USA (nbonin@sas.upenn.edu) T apply genetics to the problem of human polyglutamine-repeat disease, we recreated polyglutamineo repeat disease inDrosophila melanogaster. T do this, we expressed forms of the human gene encoding spinoo cerebellar ataxia type 3, also called Machado ^ Joseph disease (SCA-3/MJD). This gene is responsible for the most common form of human ataxia worldwide. Expression of a normal form of the MJD protein with 27 polyglutamines (MJDtr-Q27) had no phenotype. However, expression of a form of the protein with an expandedrun of 78 glutamines (MJDtr-Q78) caused late onset progressive degeneration. In addition, the MJDtr-Q78 formed abnormal protein aggregates, or nuclear inclusions (NIs), whereas the control protein was cytoplasmic. These data indicate that the mechanisms of human polyglutaminerepeat disease are conserved to Drosophila. We are currently using this model to address potential mechanisms by which themutant disease protein causes neural degeneration, as well as to de¢ne genes that can prevent polyglutamine-induced degeneration. By applying the power of Drosophila genetics to the problem of human polyglutamine-induced neural degeneration, we hope to identify ways to prevent and treat these diseases in humans. Keywords: Drosophila melanogaster; degeneration; polyglutamine-repeat disease;Machado^Joseph disease; nuclear inclusions ultimately prove feasible to use the £y to elucidate mechanisms by which polyglutamine proteins cause neural loss, as well as to de¢ne genes or compounds that can ameliorate the e¡ects of these proteins. A critical question is, if a phenotype is seen in Drosophila, to what extent does it recapitulate features of human polyglutamine-repeat disease ?
2.EXPRESSION OF A HUMAN DISEASE GENE IN THE FLY

1. INTRODUCTION

We are interested in pioneering new approaches to understand the mechanisms, and ultimately prevent, human neurodegenerative disease. T do this, we are o bringing to bear the power of genetics by developing models for human brain degenerative disease in the simple system Drosophila melanogaster (Warrick et al. 1998). Thepolyglutamine-repeat diseases are a class of human disease that results from the expansion of a polyglutamine run within the open reading frame of the disease protein. The expanded polyglutamine run is thought to confer a dominant toxic e¡ect on the otherwise unrelated proteins, leading to neuronal dysfunction and eventual cell loss (reviewed in Paulson & Fischbeck 1996). In order to address mechanisms by whichthe polyglutamine-repeat disease proteins induce neural dysfunction, as well as to identify genes that can ameliorate the e¡ects of expanded polyglutamine proteins, we asked whether it was possible to recreate human polyglutamine-repeat disease in the fruit £y Drosophila melanogaster. Drosophila has a complex nervous system, organized into neural centres much like the human brain. In addition,...