Dystonia-associated mutations cause premature degradation of torsinA protein and cell-type-specific mislocalization to the nuclear envelope
Dystonia-associated mutations cause premature degradation of torsinA protein and cell-type-specific mislocalization to the nuclear envelope
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DOI：
10.1093/hmg/ddn173
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发表时间：
2008-09-01
影响因子：
3.5
通讯作者：
Chin, Lih-Shen
中科院分区：
文献类型：
--
作者：
Giles, Lisa M.;Chen, Jue;Chin, Lih-Shen
torsinA基因框内3bp缺失导致302或303 （torsinA Delta E）位置谷氨酸残基缺失，这是早发性扭转肌张力障碍（DYT1）的主要原因。此外，torsinA基因中18bp的缺失导致残基323-328的缺失（torsinA Delta 323-8）也与肌张力障碍有关。在这里，我们报道了torsinA Delta E和torsinA Delta 323-8突变导致神经元细胞类型特异性的torsinA蛋白错定位到核膜，而不影响torsinA寡聚化。此外，两种肌张力障碍相关突变都会破坏多巴胺能细胞中的torsinA蛋白的稳定性。我们发现野生型torsinA蛋白主要通过巨噬-溶酶体途径降解。相反，torsinA Delta E和torsinA Delta 323-8突变蛋白可以通过蛋白酶体和巨噬-溶酶体途径降解。我们的研究结果表明，torsinA突变诱导的过早降解可能通过功能丧失机制促进肌张力障碍的发病机制，并强调蛋白酶体和巨噬在清除肌张力障碍相关的torsinA突变蛋白中的重要性。
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.