Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
Ann Neurol. 2010 Mar;67(3):291-300. doi: 10.1002/ana.21948.
Most neurodegenerative disorders are thought to result primarily from the accumulation of misfolded proteins, which interfere with protein homeostasis in neurons. For a subset of diseases, however, noncoding regions of RNAs assume a primary toxic gain-of-function, leading to degeneration in many tissues, including the nervous system. Here we review a series of proposed mechanisms by which noncoding repeat expansions give rise to nervous system degeneration and dysfunction. These mechanisms include transcriptional alterations and the generation of antisense transcripts, sequestration of mRNA-associated protein complexes that lead to aberrant mRNA splicing and processing, and alterations in cellular processes, including activation of abnormal signaling cascades and failure of protein quality control pathways. We place these potential mechanisms in the context of known RNA-mediated disorders, including the myotonic dystrophies and fragile X tremor ataxia syndrome, and discuss recent results suggesting that mRNA toxicity may also play a role in some presumably protein-mediated neurodegenerative disorders. Lastly, we comment on recent progress in therapeutic development for these RNA-dominant diseases.
大多数神经退行性疾病被认为主要是由于错误折叠的蛋白质积累，从而干扰神经元中的蛋白质平衡。然而，对于一部分疾病来说，RNA 的非编码区域具有主要的毒性获得性功能，导致包括神经系统在内的许多组织发生退化。在这里，我们综述了一系列提出的非编码重复扩展导致神经系统退化和功能障碍的机制。这些机制包括转录改变和反义转录本的产生，mRNA 相关蛋白复合物的隔离导致异常的 mRNA 剪接和加工，以及细胞过程的改变，包括异常信号级联的激活和蛋白质质量控制途径的失败。我们将这些潜在的机制置于已知的 RNA 介导疾病的背景下，包括肌强直性营养不良和脆性 X 震颤共济失调综合征，并讨论了最近的结果表明，mRNA 毒性也可能在一些假定的蛋白质介导的神经退行性疾病中发挥作用。最后，我们评论了这些 RNA 主导疾病的治疗开发的最新进展。
