Discipline of Genetics, School of Molecular & Biomedical Science and ARC Special Research Centre for the Molecular Genetics of Development, The University of Adelaide, Adelaide SA 5005, Australia.
Hum Mol Genet. 2013 Jul 15;22(14):2811-9. doi: 10.1093/hmg/ddt130. Epub 2013 Mar 21.
Dominantly inherited expanded repeat neurodegenerative diseases are caused by the expansion of variable copy number tandem repeat sequences in otherwise unrelated genes. Some repeats encode polyglutamine that is thought to be toxic; however, other repeats do not encode polyglutamine indicating either multiple pathogenic pathways or an alternative common toxic agent. As these diseases share numerous clinical features and expanded repeat RNA is a common intermediary, RNA-based pathogenesis has been proposed, based on its toxicity in animal models. In Drosophila, double-stranded (rCAG.rCUG∼100) RNA toxicity is Dicer dependent and generates single-stranded (rCAG)7, an entity also detected in affected Huntington's Disease (HD) brains. We demonstrate that Drosophila rCAG.rCUG∼100 RNA toxicity perturbs several pathways including innate immunity, consistent with the observation in HD that immune activation precedes neuronal toxicity. Our results show that Drosophila rCAG.rCUG∼100 RNA toxicity is dependent upon Toll signaling and sensitive to autophagy, further implicating innate immune activation. In exhibiting molecular and cellular hallmarks of HD, double-stranded RNA-mediated activation of innate immunity is, therefore, a candidate pathway for this group of human genetic diseases.
显性遗传性扩展重复神经退行性疾病是由原本无关联的基因中可变拷贝数串联重复序列的扩展引起的。一些重复序列编码聚谷氨酰胺，被认为是有毒的；然而，其他重复序列不编码聚谷氨酰胺，这表明存在多种致病途径或替代的共同毒性物质。由于这些疾病具有许多共同的临床特征，并且扩展的重复 RNA 是一种常见的中间产物，因此基于其在动物模型中的毒性，提出了基于 RNA 的发病机制。在果蝇中，双链 (rCAG.rCUG∼100) RNA 毒性依赖于 Dicer，并且产生单链 (rCAG)7，这在受影响的亨廷顿病 (HD) 大脑中也被检测到。我们证明果蝇 rCAG.rCUG∼100 RNA 毒性扰乱了包括先天免疫在内的几个途径，这与 HD 中观察到的免疫激活先于神经元毒性的观点一致。我们的结果表明，果蝇 rCAG.rCUG∼100 RNA 毒性依赖于 Toll 信号通路，并且对自噬敏感，这进一步表明先天免疫的激活。由于表现出 HD 的分子和细胞特征，双链 RNA 介导的先天免疫激活因此是这群人类遗传疾病的候选途径。
