Evert Bernd O, Vogt Ina R, Vieira-Saecker Ana M, Ozimek Lucia, de Vos Rob A I, Brunt Ewout R P, Klockgether Thomas, Wüllner Ullrich
Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
J Neuropathol Exp Neurol. 2003 Oct;62(10):1006-18. doi: 10.1093/jnen/62.10.1006.
Spinocerebellar ataxia type 3 (SCA3) is a late-onset neurodegenerative disorder caused by the expansion of a polyglutamine tract within the gene product, ataxin-3. We have previously shown that mutant ataxin-3 causes upregulation of inflammatory genes in transgenic SCA3 cell lines and human SCA3 pontine neurons. We report here a complex pattern of transcriptional changes by microarray gene expression profiling and Northern blot analysis in a SCA3 cell model. Twenty-three differentially expressed genes involved in inflammatory reactions, nuclear transcription, and cell surface-associated processes were identified. The identified corresponding proteins were analyzed by immunohistochemistry in human disease and control brain tissue to evaluate their implication in SCA3 pathogenesis. In addition to several inflammatory mediators upregulated in mutant ataxin-3 expressing cell lines and pontine neurons of SCA3 patients, we identified a profound repression of genes encoding cell surface-associated proteins in cells overexpressing normal ataxin-3. Correspondingly, these genes were upregulated in mutant ataxin-3 expressing cell lines and in pontine neurons of SCA3 patients. These findings identify for the first time target genes transcriptionally regulated by normal ataxin-3 and support the hypothesis that both loss of normal ataxin-3 and gain of function through protein-protein interacting properties of mutant ataxin-3 contribute to SCA3 pathogenesis.
3型脊髓小脑共济失调（SCA3）是一种迟发性神经退行性疾病，由基因产物ataxin-3内的多聚谷氨酰胺序列扩增引起。我们之前已经表明，突变型ataxin-3会导致转基因SCA3细胞系和人类SCA3脑桥神经元中炎症基因的上调。我们在此报告了通过微阵列基因表达谱分析和Northern印迹分析在SCA3细胞模型中发现的复杂转录变化模式。鉴定出了23个参与炎症反应、核转录和细胞表面相关过程的差异表达基因。通过免疫组织化学在人类疾病和对照脑组织中分析了鉴定出的相应蛋白质，以评估它们在SCA3发病机制中的作用。除了在表达突变型ataxin-3的细胞系和SCA3患者的脑桥神经元中上调的几种炎症介质外，我们还发现在过表达正常ataxin-3的细胞中，编码细胞表面相关蛋白的基因受到显著抑制。相应地，这些基因在表达突变型ataxin-3的细胞系和SCA3患者的脑桥神经元中上调。这些发现首次确定了受正常ataxin-3转录调控的靶基因，并支持这样的假设，即正常ataxin-3的缺失以及突变型ataxin-3通过蛋白质-蛋白质相互作用特性获得的功能都有助于SCA3的发病机制。
