Jl. Marsh et al., Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila, HUM MOL GEN, 9(1), 2000, pp. 13-25
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.