Human Molecular Genetics Advance Access originally published online on June 14, 2008
Human Molecular Genetics 2008 17(17):2712-2722; doi:10.1093/hmg/ddn173
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Dystonia-associated mutations cause premature degradation of torsinA protein and cell-type-specific mislocalization to the nuclear envelope
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322-3090, USA
* To whom correspondence should be addressed. Tel: +1 4047270361; Fax: +1 4047270365; Email: chinl{at}pharm.emory.edu
Received March 14, 2008; Revised May 20, 2008; Accepted June 10, 2008
An in-frame 3 bp deletion in the torsinA gene resulting in the loss of a glutamate residue at position 302 or 303 (torsinA 
E) is the major cause for early-onset torsion dystonia (DYT1). In addition, an 18 bp deletion in the torsinA gene resulting in the loss of residues 323–328 (torsinA 323–8) has also been associated with dystonia. Here we report that torsinA E and torsinA 323–8 mutations cause neuronal cell-type-specific mislocalization of torsinA protein to the nuclear envelope without affecting torsinA oligomerization. Furthermore, both dystonia-associated mutations destabilize torsinA protein in dopaminergic cells. We find that wild-type torsinA protein is degraded primarily through the macroautophagy–lysosome pathway. In contrast, torsinA E and torsinA 323–8 mutant proteins are degraded by both the proteasome and macroautophagy–lysosome pathways. Our findings suggest that torsinA mutation-induced premature degradation may contribute to the pathogenesis of dystonia via a loss-of-function mechanism and underscore the importance of both the proteasome and macroautophagy in the clearance of dystonia-associated torsinA mutant proteins.
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