Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 101, Issue 20, Pages 7612-7617Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0308760101
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Funding
- NIGMS NIH HHS [R01 GM029647, GM29647] Funding Source: Medline
- NINDS NIH HHS [R01 NS028384, NS28384] Funding Source: Medline
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Early-onset torsion dystonia, a CNS-based movement disorder, is usually associated with a single amino acid deletion (DeltaE302/303) in the protein torsinA. TorsinA is an AAA+ ATPase in the endoplasmic reticulum, but what it does is unknown. Here, we use torsinA mutants with defects in ATP hydrolysis (E171Q, ATP-bound) and ATP binding (K108A, ATP-free) to probe torsinA's normal cellular function. Surprisingly, ATP-bound torsinA is recruited to the nuclear envelope (NE) of transfected cells, where it alters connections between inner and outer nuclear membranes. In contrast, ATP-free torsinA is diffusely distributed throughout the endoplasmic reticulum and has no effect on the NE. Among AAA+ ATPases, affinity for substrates is high in the ATIP-bound and low in the ATIP-free state, leading us to propose that component(s) of the NE may be substrates for torsinA. We also find that the disease-promoting DeltaE302/303 mutant is in the NE, and that this relocalization, as well as the mutant's previously described ability to induce membranous inclusions, is eliminated by the K108A ATP-bincling mutation. These results suggest that changes in interactions involving torsinA in the NE could be important for the pathogenesis of dystonia and point to torsinA and related proteins as a class of ATPases that may operate in the NE.
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