Centre for Cancer Therapeutics, Ottawa Hospital Research Institute Ottawa, ON, Canada ; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa Ottawa, ON, Canada.
Front Genet. 2013 Aug 14;4:149. doi: 10.3389/fgene.2013.00149. eCollection 2013.
Whereas many cases of neurodegenerative disease feature the abnormal accumulation of protein, an abundance of recent literature highlights loss of RNA homeostasis as a ubiquitous and central feature of pathological states. In some diseases expanded repeats have been identified in non-coding regions of disease-associated transcripts, calling into question the relevance of protein in the disease mechanism. We review the literature in support of a hypothesis that intrinsically disordered proteins (proteins that lack a stable three dimensional conformation) are particularly sensitive to an age-related decline in maintenance of protein homeostasis. The potential consequences for structurally disordered RNA-binding proteins are explored, including their aggregation into complexes that could be transmitted through a prion-like mechanism. We propose that the spread of ribonucleoprotein complexes through the nervous system could propagate a neuronal error catastrophe at the level of RNA metabolism.
虽然许多神经退行性疾病的特征是蛋白质的异常积累，但大量最近的文献强调了 RNA 内稳平衡的丧失是病理状态的普遍和核心特征。在一些疾病中，已经在与疾病相关的转录本的非编码区域中鉴定出了扩展的重复序列，这使得蛋白质在疾病机制中的相关性受到质疑。我们回顾了文献，支持这样一种假设，即无规则蛋白质（缺乏稳定的三维构象的蛋白质）对与年龄相关的蛋白质内稳平衡维持的下降特别敏感。还探讨了结构无序 RNA 结合蛋白的潜在后果，包括它们聚集成复合物，这些复合物可能通过类朊病毒机制传播。我们提出，核糖核蛋白复合物在神经系统中的传播可能会在 RNA 代谢水平上引发神经元错误灾难。
