Expansion of the polyQ repeat in ataxin-2 alters its Golgi localization, disrupts the Golgi complex and causes cell death
Expansion of the polyQ repeat in ataxin-2 alters its Golgi localization, disrupts the Golgi complex and causes cell death
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DOI：
10.1093/hmg/ddg175
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发表时间：
2003-07-01
影响因子：
3.5
通讯作者：
Pulst, SM
中科院分区：
文献类型：
--
作者：
Huynh, DP;Yang, HT;Pulst, SM
脊髓小脑性共济失调2型（SCA 2）是由共济失调蛋白2（SCA 2基因产物）中多聚谷氨酰胺（polyQ）重复序列扩增引起的。与其他polyQ疾病相比，SCA 2中的核内包涵体并不突出。在靶向浦肯野细胞表达突变型共济失调蛋白-2的动物模型中，观察到神经元功能障碍和形态学变化，而没有形成核内聚集体。在这份报告中，我们研究了SCA 2发病机制的细胞模型。我们证实SCA 2基因产物ataxin-2主要位于高尔基体。在共济失调蛋白-2的ER-出口和trans-Golgi信号的删除导致改变亚细胞分布。表达全长ataxin-2与扩大重复破坏正常形态的高尔基复合体和共定位与高尔基标记丢失。只有当polyQ重复扩增到104个谷氨酰胺时才能看到核内包涵体，即使这样，也只在少数细胞中观察到。与正常共济失调蛋白-2相比，在PC 12和COS 1细胞中具有扩展重复序列的共济失调蛋白-2的表达增加了细胞死亡，并升高了活化的caspase-3和TUNEL阳性细胞的水平。这些结果表明突变型共济失调蛋白2介导的细胞死亡与高尔基复合体的稳定性之间存在联系。核内聚集体的形成对于全长突变型共济失调蛋白-2的表达所引起的体外细胞死亡不是必需的。
Spinocerebellar ataxia type 2 (SCA2) is caused by the expansion of a polyglutamine (polyQ) repeat in ataxin-2, the SCA2 gene product. In contrast to other polyQ diseases, intranuclear inclusions are not prominent in SCA2. In animal models with expression of mutant ataxin-2 targeted to Purkinje cells, neuronal dysfunction and morphologic changes are observed without the formation of intranuclear aggregates. In this report, we investigated the mechanisms underlying SCA2 pathogenesis using cellular models. We confirmed that the SCA2 gene product, ataxin-2, was predominantly located in the Golgi apparatus. Deletion of ER-exit and trans-Golgi signals in ataxin-2 resulted in an altered subcellular distribution. Expression of full-length ataxin-2 with an expanded repeat disrupted the normal morphology of the Golgi complex and colocalization with Golgi markers was lost. Intranuclear inclusions were only seen when the polyQ repeat was expanded to 104 glutamines, and even then were only observed in a small minority of cells. Expression of ataxin-2 with expanded repeats in PC12 and COS1 cells increased cell death compared with normal ataxin-2 and elevated the levels of activated caspase-3 and TUNEL-positive cells. These results suggest a link between cell death mediated by mutant ataxin-2 and the stability of the Golgi complex. The formation of intranuclear aggregates is not necessary for in vitro cell death caused by expression of full-length mutant ataxin-2.