Molecular Pathology of Polyalanine Expansion Disorders: New Perspectives from Mouse Models

Disease-causing polyalanine (PA) expansion mutations have been identified in nine genes, eight of which encode transcription factors (TFs) with important roles in development. In vitro and cell overexpression studies have shown that expanded PA tracts result in protein misfolding and the formation of aggregates. This feature of PA proteins is reminiscent of the related polyglutamine (PQ) disease proteins, which have been shown to cause disease via a gain-of-function (GOF) mechanism. However, in sharp contrast to PQ disorders, the disease phenotypes associated with PA mutations are more consistent with a LOF and/or mild GOF mechanism, suggesting that their molecular pathology is inherently different to PQ disorders. Elucidating the cellular impact of PA mutations in vivo has been difficult to address as, unlike the late-onset polyglutamine disorders, all PA disorders associated with TF gene mutations are congenital. However, in recent years, significant advances have been made through the analysis of engineered (knock-in) and spontaneous PA mouse models. Here we review these recent findings and propose an updated model of the molecular and cellular mechanism of PA disorders that incorporates both LOF and GOF features.