Local protein unfolding and pathogenesis of polyglutamine-expansion diseases.

Polyglutamine expansion diseases are caused by the abnormal lengthening of a glutamine repeat in the respective protein and are believed to progress via a common mechanism. Here a hypothesis based on protein unfolding is formulated to enhance understanding of the pathogenesis of these diseases. Nine disease proteins of this family were investigated with an unfolding prediction protocol based on calculating the net charge and the overall hydrophobicity from the primary sequence. These protein sequences were analysed with and without their respective nonpathogenic glutamine repeats. When full-length protein sequences were studied, the calculations suggest that unexpanded polyglutamine repeats have a minimal effect on the global folding state of the parent proteins. When confined to a local context approximating the size of a single-protein domain, the calculations suggest that all nine sequences including a normal-length polyglutamine repeat correspond to the unfolded state. The unfolding predictions were applied to two model systems and were found to be consistent with published experimental data. Despite its simplicity, this analysis can be extended to simulate repeat length-dependent protein unfolding, an event speculated to precede aggregation and disease progression. This work highlights the correlation between glutamine repeats and protein unfolding and provides insight into the as yet unknown polyglutamine expansion pathogenic mechanism.