Nuclear poly-glutamine aggregates rupture the nuclear envelope and hinder its repair

Abstract

Huntingtons disease (HD) is caused by a poly-glutamine expansion of the huntingtin protein, resulting in the formation of poly-glutamine aggregates. The mechanisms of toxicity that result in the complex HD pathology remain only partially understood. Here we show that nuclear polyglutamine aggregates deform the nuclear envelope (NE) and induce NE ruptures that are often repaired incompletely. These ruptures coincide with deformations of the nuclear lamina and lead to lamina scar formation. Expansion microscopy enabled resolving the ultrastructure of nuclear aggregates and revealed polyglutamine fibrils sticking into the cytosol at rupture sites, suggesting a mechanism for incomplete repair. These findings implicate nuclear polyQ aggregate-induced loss of NE integrity as a potential contributing factor to Huntingtons disease and other polyglutamine diseases. One-sentence summaryAggregates associated with Huntingtons Disease induce ruptures of the nuclear envelop that compromise its barrier function