Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Neuron. 2010 Sep 23;67(6):929-35. doi: 10.1016/j.neuron.2010.08.022.
Glutamine tract expansion triggers nine neurodegenerative diseases by conferring toxic properties to the mutant protein. In SCA1, phosphorylation of ATXN1 at Ser776 is thought to be key for pathogenesis. Here, we show that replacing Ser776 with a phosphomimicking Asp converted ATXN1 with a wild-type glutamine tract into a pathogenic protein. ATXN1[30Q]-D776-induced disease in Purkinje cells shared most features with disease caused by ATXN1[82Q] having an expanded polyglutamine tract. However, in contrast to disease induced by ATXN1[82Q] that progresses to cell death, ATXN1[30Q]-D776 failed to induce cell death. These results support a model where pathogenesis involves changes in regions of the protein in addition to the polyglutamine tract. Moreover, disease initiation and progression to neuronal dysfunction are distinct from induction of cell death. Ser776 is critical for the pathway to neuronal dysfunction, while an expanded polyglutamine tract is essential for neuronal death.
谷氨酰胺重复序列扩展通过赋予突变蛋白毒性来引发九种神经退行性疾病。在 SCA1 中，ATXN1 在丝氨酸 776 处的磷酸化被认为是发病机制的关键。在这里，我们表明，用磷酸模拟的天冬氨酸取代丝氨酸 776 将具有野生型谷氨酰胺重复序列的 ATXN1 转化为致病性蛋白。具有扩展的多聚谷氨酰胺重复序列的 ATXN1[82Q] 引起的浦肯野细胞疾病与 ATXN1[30Q]-D776 诱导的疾病具有大多数特征。然而，与由 ATXN1[82Q] 诱导导致细胞死亡的疾病相反，ATXN1[30Q]-D776 未能诱导细胞死亡。这些结果支持这样一种模型，即发病机制涉及除多聚谷氨酰胺重复序列之外的蛋白质区域的变化。此外，疾病的起始和向神经元功能障碍的进展与诱导细胞死亡不同。丝氨酸 776 对于神经元功能障碍的途径至关重要，而扩展的多聚谷氨酰胺重复序列对于神经元死亡是必不可少的。
