Local protein unfolding and pathogenesis of polyglutamine-expansion diseases

ABSTRACT Polyglutamine expansion diseases are caused by the abnormal lengthening of a glu-tamine repeat in the respective protein and are believed to progress via a commonmechanism. Here a hypothesis based on protein unfolding is formu-lated to enhance understanding of the pathogenesis of these diseases. Nine disease proteins of this fam-ily 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 predictionswere 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 specu-lated to precede aggregation and disease progres-sion. This work highlights the correlation between glutamine repeats and protein unfolding and pro-vides insight into the as yet unknown polyglu-tamine expansion pathogenic mechanism. Protein