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bioRxiv · 10.64898/2026.08.17.745292

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

Cui, H.·Duan, Y.·Islam, M. K.·Hosain, M. A.·Li, J.·Lu, X.·Ding, B.
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Abstract

Childhood-onset DYT1 dystonia is a neurodevelopmental movement disorder caused by a three-base-pair deletion ({Delta}GAG; {Delta}E) in the TOR1A gene, which encodes TorsinA, a membrane-associated AAA+ (ATPase associated with diverse cellular activities) ATPase. However, the mechanisms by which the {Delta}E mutation causes neuronal dysfunction remain poorly understood. Using patient-derived neurons, we previously demonstrated that TorsinA-{Delta}E 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 {Delta}E 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 {Delta}E 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-{Delta}E and XPO1 as a mechanism contributing to NCT dysfunction in DYT1 dystonia and establish the HS-dependent {Delta}E-XPO1 interaction as a potential therapeutic target.

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Cui, H., Duan, Y., Islam, M. K., Hosain, M. A., Li, J., Lu, X., Ding, B.. 2026-08-21. Dystonia-associated TorsinA-ΔE mutation induces a gain-of-function interaction with XPO1 via its N-terminal hydrophobic segment. https://doi.org/10.64898/2026.08.17.745292

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