Journal
HUMAN MOLECULAR GENETICS
Volume 17, Issue 17, Pages 2712-2722Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddn173
Keywords
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Funding
- National Institutes of Health [NS054334, AG021489, NS050650, ES015813]
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An in-frame 3 bp deletion in the torsinA gene resulting in the loss of a glutamate residue at position 302 or 303 (torsinA Delta 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 Delta 323-8) has also been associated with dystonia. Here we report that torsinA Delta E and torsinA Delta 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 Delta E and torsinA Delta 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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