Atypical nuclear envelope condensates linked to neurological disorders reveal nucleoporin-directed chaperone activities

DYT1 dystonia is a debilitating neurological movement disorder arising from mutation in the AAA+ ATPase TorsinA. The hallmark of Torsin dysfunction is nuclear envelope blebbing resulting from defects in nuclear pore complex biogenesis. Whether blebs actively contribute to disease manifestation is unknown. We report that FG-nucleoporins in the bleb lumen form aberrant condensates and contribute to DYT1 dystonia by provoking two proteotoxic insults. Short-lived ubiquitylated proteins that are normally rapidly degraded partition into the bleb lumen and become stabilized. In addition, blebs selectively sequester a specific HSP40-HSP70 chaperone network that is modulated by the bleb component MLF2. MLF2 suppresses the ectopic accumulation of FG-nucleoporins and modulates the selective properties and size of condensates in vitro. Our study identifies dual mechanisms of proteotoxicity in the context of condensate formation and establishes FG-nucleoporin-directed activities for a nuclear chaperone network. Kuiper et al. and Prophet et al. implicate DNAJB6/HSP70 chaperone activities in the biogenesis of the nuclear pore complex permeability barrier and find that disease-linked nuclear envelope blebs are enriched in nucleoporin and chaperone condensates.

Automated summary

DYT1 dystonia is a neurological movement disorder caused by a mutation in the TorsinA gene. Our study reveals that aberrant condensates formed by nucleoporins in nuclear envelope blebs and the activity of a nuclear chaperone network contribute to the development of DYT1 dystonia.