Dystonia-associated TorsinA-ΔE mutation induces a gain-of-function interaction with XPO1 via its N-Terminal hydrophobic segment

Childhood-onset DYT1 dystonia is a neurodevelopmental movement disorder caused by a three-base-pair deletion (ΔGAG; ΔE) in the TOR1A gene, which encodes TorsinA, a membrane-associated AAA+ (ATPase associated with diverse cellular activities) ATPase. However, the mechanisms by which the ΔE mutation causes neuronal dysfunction remain poorly understood. Using patient-derived neurons, we previously demonstrated that TorsinA-ΔE disrupts the nucleocytoplasmic transport (NCT) of both RNA and protein cargos. In the present study, proteomic analysis of induced human motor neurons revealed a markedly enhanced association between ΔE and exportin 1 (XPO1), a major nuclear export receptor. This aberrant association was enriched at the nuclear envelope and accompanied by impaired XPO1-mediated nuclear export. By integrating AlphaFold-based structural modeling with molecular, biochemical, and cellular analyses, we identified the N-terminal hydrophobic segment (HS) of TorsinA as a critical contributor to its interaction with XPO1. Deletion of the HS from ΔE reduced its association with XPO1, altered its nuclear envelope enrichment, and restored nuclear export. Moreover, expression of HS-derived peptides in patient-derived DYT1 neurons improved nuclear export, neurite outgrowth and branching, maturation-associated gene expression, and neuronal survival. Together, these findings identify an aberrant gain-of-function association between TorsinA-ΔE and XPO1 as a mechanism contributing to NCT dysfunction in DYT1 dystonia and establish the HS-dependent ΔE-XPO1 interaction as a potential therapeutic target.