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The Journal of Neuroscience, March 17, 2004, 24(11):2593-2601; doi:10.1523/JNEUROSCI.4461-03.2004

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Neurobiology of Disease
Aberrant Cellular Behavior of Mutant TorsinA Implicates Nuclear Envelope Dysfunction in DYT1 Dystonia

Pedro Gonzalez-Alegre and Henry L. Paulson

Department of Neurology, Carver College of Medicine at the University of Iowa, Iowa City, Iowa 52242

Torsion dystonia-1 (DYT1) dystonia, the most common inherited form of dystonia, is caused by a three base pair deletion that eliminates a single amino acid from the disease protein, torsinA. TorsinA is an "AAA" protein thought to reside in the endoplasmic reticulum (ER), yet both its cellular function and the basis for neuronal dysfunction in DYT1 remain unknown. A clue to disease pathogenesis is the fact that mutant, but not wild-type, torsinA forms membranous inclusions in cell culture. To explore the pathobiology of DYT1 dystonia, we generated PC12 neural cell lines that inducibly express wild-type or mutant torsinA. Although in this model torsinA displays some properties consistent with ER localization, mutant torsinA also accumulates in the nuclear envelope (NE), a structure contiguous with cytoplasmic ER. Consistent with this, membranous inclusions formed by mutant torsinA are shown to derive not from the ER, as thought previously, but from the NE. We demonstrate further that torsinA forms different disulfide-linked complexes that may be linked functionally to subcellular localization in the NE versus cytoplasmic ER. Despite mutant TA accumulation in NE structures, nucleocytoplasmic transport of a reporter protein was unaffected. These findings, together with parallel studies failing to demonstrate perturbation of ER function, implicate the NE as a primary site of dysfunction in DYT1. DYT1 dystonia can be added to the growing list of inherited neurological disorders involving the NE.

Key words: dystonia; torsinA; DYT1; nuclear envelope; karmellas; endoplasmic reticulum

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Received Oct 1, 2003; revised January 14, 2004; accepted January 23, 2004.

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