Dystonia-associated mutations cause premature degradation of torsinA protein and cell-type-specific mislocalization to the nuclear envelope

被引:65
作者
Giles, Lisa M. [1 ]
Chen, Jue [1 ]
Li, Lian [1 ]
Chin, Lih-Shen [1 ]
机构
[1] Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1093/hmg/ddn173
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2712 / 2722
页数:11
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