Gatchel Jennifer R, Watase Kei, Thaller Christina, Carson James P, Jafar-Nejad Paymaan, Shaw Chad, Zu Tao, Orr Harry T, Zoghbi Huda Y
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1291-6. doi: 10.1073/pnas.0711257105. Epub 2008 Jan 23.
Polyglutamine diseases are inherited neurodegenerative disorders caused by expansion of CAG repeats encoding a glutamine tract in the disease-causing proteins. There are nine disorders, each having distinct features but also clinical and pathological similarities. In particular, spinocerebellar ataxia type 1 and 7 (SCA1 and SCA7) patients manifest cerebellar ataxia with degeneration of Purkinje cells. To determine whether the disorders share molecular pathogenic events, we studied two mouse models of SCA1 and SCA7 that express the glutamine-expanded protein from the respective endogenous loci. We found common transcriptional changes, with down-regulation of insulin-like growth factor binding protein 5 (Igfbp5) representing one of the most robust changes. Igfbp5 down-regulation occurred in granule neurons through a non-cell-autonomous mechanism and was concomitant with activation of the insulin-like growth factor (IGF) pathway and the type I IGF receptor on Purkinje cells. These data define one common pathogenic response in SCA1 and SCA7 and reveal the importance of intercellular mechanisms in their pathogenesis.
多聚谷氨酰胺疾病是由编码致病蛋白中谷氨酰胺序列的CAG重复序列扩增引起的遗传性神经退行性疾病。这类疾病共有九种，每种都有独特的特征，但在临床和病理方面也有相似之处。特别是，1型和7型脊髓小脑共济失调（SCA1和SCA7）患者表现出小脑共济失调，并伴有浦肯野细胞变性。为了确定这些疾病是否共享分子致病事件，我们研究了两种SCA1和SCA7小鼠模型，它们从各自的内源性基因座表达谷氨酰胺扩增蛋白。我们发现了共同的转录变化，其中胰岛素样生长因子结合蛋白5（Igfbp5）的下调是最显著的变化之一。Igfbp5的下调通过非细胞自主机制在颗粒神经元中发生，并与胰岛素样生长因子（IGF）途径的激活以及浦肯野细胞上的I型IGF受体的激活同时出现。这些数据确定了SCA1和SCA7中的一种共同致病反应，并揭示了细胞间机制在其发病机制中的重要性。
