Consequences of the DYT1 mutation on torsinA oligomerization and degradation.
Consequences of the DYT1 mutation on torsinA oligomerization and degradation.
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DOI：
10.1016/j.neuroscience.2008.09.028
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发表时间：
2008-12-02
期刊：
影响因子：
3.3
通讯作者：
Gonzalez-Alegre, P.
中科院分区：
文献类型：
--
作者：
Gordon, K. L.;Gonzalez-Alegre, P.
DYT1是最常见的遗传性肌张力障碍，这是一种神经系统综合症，会导致不随意肌肉收缩。这种常染色体显性疾病是由蛋白质torsinA羧基末端附近的谷氨酸缺失引起的。基于细胞和动物的研究已经表明，DYT1突变如何导致突变的torsinA从内质网重新分布到核膜，通过对野生型蛋白的显性负作用起作用。因此，野生型：突变型torsinA表达比对疾病发病机制很重要，而影响它的事件，如每种蛋白质的差异降解过程，可能会调节DYT1的病理生物学。DYT1突变也会触发torsinA中异常分子间二硫键的形成，尽管这一发现的意义尚不清楚。蛋白质质量控制机制如何处理torsinA，以及这一过程是否受到其异常寡聚化的影响仍然未知。在这里，我们首先探索了疾病相关突变如何影响torsinA的分解代谢过程，证明了两种形式的torsinA之间亚细胞定位的差异导致了它们降解途径的差异，而torsinA通常通过自噬循环，蛋白酶体也是有效清除突变形式所必需的。随后，我们确定突变体torsinA的异常二硫键依赖性寡聚化不是其重新分配到核膜的结果，而是突变的直接后果。最后，我们确定突变体torsinA低聚物中二硫键的存在干扰了蛋白酶体对其的降解，因此依赖自噬作为清除的主要途径。总之，dyt1连接的torsinA的异常亚细胞定位和寡聚化影响了其分解代谢过程，从而为通过对蛋白质降解途径的药理学操作来调节野生型：突变型torsinA比率打开了大门。
DYT1 is the most common inherited dystonia, a neurological syndrome that causes disabling involuntary muscle contractions. This autosomal dominant disease is caused by a glutamic acid deletion near the carboxy-terminus in the protein torsinA. Cell and animal based studies have shown how the DYT1 mutation causes mutant torsinA to redistribute from the endoplasmic reticulum to the nuclear envelope, acting through a dominant negative effect over the wild type protein. As a result, the wild type:mutant torsinA expression ratio would be important for disease pathogenesis, and events that influence it, such as a differential degradation process for each protein, might modulate DYT1 pathobiology. The DYT1 mutation also triggers the formation of abnormal intermolecular disulfide bonds in torsinA, although the significance of this finding is unclear. How the protein quality control machinery handles torsinA, and whether this process is affected by its abnormal oligomerization remain unknown. Here, we first explored how the disease-linked mutation influences the catabolic process of torsinA, demonstrating that the differences in subcellular localization between both forms of torsinA lead to divergences in their degradation pathways and, whereas torsinA is normally recycled through autophagy, the proteasome is also required for the efficient clearance of the mutated form. Subsequently, we determined that the abnormal disulfide bond-dependent oligomerization of mutant torsinA is not a result of its redistribution to the nuclear envelope, but a direct consequence of the mutation. Finally, we established that the presence of disulfide links in mutant torsinA oligomers interfere with their degradation by the proteasome, thus relying on autophagy as the main pathway for clearance. In conclusion, the abnormal subcellular localization and oligomerization of DYT1-linked torsinA influences its catabolic process, opening the door to the modulation of the wildtype:mutant torsinA ratio through pharmacological manipulation of protein degradation pathways.
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3.5
作者：
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通讯作者：
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发表时间：
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