Abou-Sleymane Gretta, Chalmel Frédéric, Helmlinger Dominique, Lardenois Aurélie, Thibault Christelle, Weber Chantal, Mérienne Karine, Mandel Jean-Louis, Poch Olivier, Devys Didier, Trottier Yvon
Department of Molecular Pathology, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/ULP, BP10142, 67404 Illkirch Cédex, CU de Strasbourg, France.
Hum Mol Genet. 2006 Mar 1;15(5):691-703. doi: 10.1093/hmg/ddi483. Epub 2006 Jan 24.
Huntington's disease (HD) and spinocerebellar ataxia type 7 (SCA7) belong to a group of inherited neurodegenerative diseases caused by polyglutamine (polyQ) expansion in corresponding proteins. Transcriptional alteration is a unifying feature of polyQ disorders; however, the relationship between polyQ-induced gene expression deregulation and degenerative processes remains unclear. R6/2 and R7E mouse models of HD and SCA7, respectively, present a comparable retinal degeneration characterized by progressive reduction of electroretinograph activity and important morphological changes of rod photoreceptors. The retina, which is a simple central nervous system tissue, allows correlating functional, morphological and molecular defects. Taking advantage of comparing polyQ-induced degeneration in two retina models, we combined gene expression profiling and molecular biology techniques to decipher the molecular pathways underlying polyQ expansion toxicity. We show that R7E and R6/2 retinal phenotype strongly correlates with loss of expression of a large cohort of genes specifically involved in phototransduction function and morphogenesis of differentiated rod photoreceptors. Accordingly, three key transcription factors (Nrl, Crx and Nr2e3) controlling rod differentiation genes, hence expression of photoreceptor specific traits, are down-regulated. Interestingly, other transcription factors known to cause inhibitory effects on photoreceptor differentiation when mis-expressed, such as Stat3, are aberrantly re-activated. Thus, our results suggest that independently from the protein context, polyQ expansion overrides the control of neuronal differentiation and maintenance, thereby causing dysfunction and degeneration.
亨廷顿舞蹈病（HD）和7型脊髓小脑共济失调（SCA7）属于一类由相应蛋白质中多聚谷氨酰胺（polyQ）扩增引起的遗传性神经退行性疾病。转录改变是多聚谷氨酰胺疾病的一个共同特征；然而，多聚谷氨酰胺诱导的基因表达失调与退行性过程之间的关系仍不清楚。HD和SCA7的R6/2和R7E小鼠模型分别表现出类似的视网膜变性，其特征是视网膜电图活性逐渐降低以及视杆光感受器出现重要的形态学变化。视网膜作为一种简单的中枢神经系统组织，有助于将功能、形态和分子缺陷联系起来。利用比较两种视网膜模型中多聚谷氨酰胺诱导的变性，我们结合基因表达谱分析和分子生物学技术来解读多聚谷氨酰胺扩增毒性背后的分子途径。我们发现，R7E和R6/2视网膜表型与一大批专门参与光转导功能和分化视杆光感受器形态发生的基因表达缺失密切相关。相应地，控制视杆细胞分化基因从而影响光感受器特异性特征表达的三个关键转录因子（Nrl、Crx和Nr2e3）被下调。有趣的是，其他一些已知在错误表达时会对视杆细胞分化产生抑制作用的转录因子，如Stat3，却被异常重新激活。因此，我们的结果表明，独立于蛋白质背景，多聚谷氨酰胺扩增会破坏神经元分化和维持的控制，从而导致功能障碍和变性。
