When more is not better: Expanded polyglutamine domains in neurodegenerative disease

Abstract

Expanded polyglutamine domains are implicated in nine progressive neurodegenerative disorders, of which Huntington's disease is the best known. Nine proteins are associated with these disorders; the proteins share no sequence or structural homology except for a polyglutamine tract that is unusually lengthened in those affected by the diseases. A common feature of these disorders is the presence of inclusions containing the associated protein in the nucleus or cytoplasm of affected neurons. Why do expanded polyglutamine proteins cause neurodegenerative disease? This remains an unsettled question, but most researchers now suspect that long polyglutamine domains cause protein misfolding and aggregation, and that there is a gain-of-toxic-function upon aggregation. Two specific hypotheses attribute toxicity to sequestration of transcription factors and subsequent transcriptome dysregulation, or to overloading and subsequent impairment of the ubiquitin-proteasome system, leading to loss of protein homeostasis. Most but not all evidence points to aggregation as an essential component of toxicity; many researchers suggest that less-ordered, smaller, and/or soluble intermediates are the toxic species. Detailed biophysical studies with synthetic peptides and proteins have uncovered many details about the conformation of polyglutamine domains, and the structure of aggregates, but much remains to be done. Significant evidence points to the important role of protein context on modulating the effect of polyglutamine. Although early studies with model peptides suggested that aggregation occurred by a simple nucleation-elongation mechanism, more recent studies clearly indicate that a more complex pathway is involved. There are a few other expanded poly-amino-acid domains associated with disease, particularly polyalanine, although these are much less common than polyglutamine-related disorders, and even less is known about them. A comparison of expanded polyglutamine and expanded polyalanine may illuminate their common features as well as those features unique to each.