Polyglutamine expansions in certain
proteins are the genetic determinants for nine distinct progressive
neurodegenerative disorders and resultant age-related
dementia. In these cases, neurodegeneration is due to the aggregation propensity and resultant toxic properties of the
polyglutamine-containing
proteins. We are interested in elucidating the underlying mechanisms of toxicity of the
protein ataxin-3, in which a
polyglutamine expansion is the genetic determinant for
Machado-Joseph Disease (MJD), also referred to as
spinocerebellar ataxia 3 (SCA3). To this end, we have developed a novel model for
ataxin-3 protein aggregation, by expressing a disease-related
polyglutamine-containing fragment of
ataxin-3 in the genetically tractable body wall muscle cells of the model system C. elegans. Here, we demonstrate that this
ataxin-3 fragment aggregates in a
polyQ length-dependent manner in C. elegans muscle cells and that this aggregation is associated with cellular dysfunction. However, surprisingly, this aggregation and resultant toxicity was not influenced by aging. This is in contrast to
polyglutamine peptides alone whose aggregation/toxicity is highly dependent on age. Thus, the data presented here not only describe a new
polyglutamine model, but also suggest that
protein context likely influences the cellular interactions of the
polyglutamine-containing
protein and thereby modulates its toxic properties.