Huynh Duong P, Yang Hai-Tao, Vakharia Hema, Nguyen Dung, Pulst Stefan M
Rose Moss Laboratory for Parkinson and Neurodegenerative Diseases, Burns and Allen Research Institute,UCLA School of Medicine, Los Angeles, California, USA.
Hum Mol Genet. 2003 Jul 1;12(13):1485-96. doi: 10.1093/hmg/ddg175.
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.
2型脊髓小脑共济失调（SCA2）由SCA2基因产物ataxin-2中的多聚谷氨酰胺（polyQ）重复序列扩增引起。与其他多聚谷氨酰胺疾病不同，SCA2中核内包涵体并不突出。在将突变型ataxin-2表达靶向浦肯野细胞的动物模型中，观察到神经元功能障碍和形态学变化，但未形成核内聚集体。在本报告中，我们使用细胞模型研究了SCA2发病机制的潜在机制。我们证实，SCA2基因产物ataxin-2主要位于高尔基体。ataxin-2中内质网出口和反式高尔基体信号的缺失导致亚细胞分布改变。具有扩增重复序列的全长ataxin-2的表达破坏了高尔基体复合体的正常形态，并且与高尔基体标记物的共定位丧失。仅当多聚谷氨酰胺重复序列扩增至104个谷氨酰胺时才可见核内包涵体，即便如此，也仅在少数细胞中观察到。与正常ataxin-2相比，在PC12和COS1细胞中表达具有扩增重复序列的ataxin-2会增加细胞死亡，并提高活化的半胱天冬酶-3水平和TUNEL阳性细胞数量。这些结果表明，突变型ataxin-2介导的细胞死亡与高尔基体复合体的稳定性之间存在联系。全长突变型ataxin-2表达引起的体外细胞死亡并不需要形成核内聚集体。
