Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila

Several dominant, late-onset neurodegenerative diseases (e.g, Huntington's disease) are caused by expansion of polyglutamine (polyQ) repeats within sp ecific proteins. The diverse, yet overlapping, pathology of these diseases could be due to novel deleterious functions unique to each protein or to a common pathophysiology mediated by the long polyQ chains themselves. By eng ineering Drosophila to express different polyQ peptides, we find that expan ded polyQ chains alone are intrinsically cytotoxic and cause neuronal degen eration and early adult death. We further find that this intrinsic toxicity is dependent on cell type and polyQ length and that the inclusion of other amino acids modifies and reduces toxicity. This is the first in vivo evide nce that polyQs, when removed from their disease gene context, cause neurot oxicity. These studies provide a basis for understanding the diverse clinic al presentations in terms of the intrinsic cytotoxic effect of polyQ peptid es being modulated by protein context. parallel experiments in which cytoto xic polyQ expansions were engineered into Dishevelled, a Drosophila protein containing a naturally occurring polyQ tract, strongly suggest that the ef fect of a toxic polyQ peptide can be neutralized by protein context, This a nimal model provides a simple and effective means of screening for therapeu tics that relieves the polyQ-induced lethality, independent of any particul ar disease gene. By quantifying the degree of lethality in several transgen ic lines, we have identified a number of genetically modified strains that are suitable for eventual testing of compounds or genes that ameliorate the pathology of polyQ peptides.