Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan.
J Neurochem. 2023 Jul;166(2):156-171. doi: 10.1111/jnc.15847. Epub 2023 Jun 5.
An hexanucleotide repeat expansion mutation in the non-coding region of C9orf72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis. This mutation is estimated to be the most frequent genetic cause of these currently incurable diseases. Since the mutation causes autosomal dominantly inherited diseases, disease cascade essentially starts from the expanded DNA repeats. However, molecular disease mechanism is inevitably complex because possible toxic entity for the disease is not just functional loss of translated C9ORF72 protein, if any, but potentially includes bidirectionally transcribed expanded repeat containing RNA and their unconventional repeat-associated non-AUG translation products in all possible reading frames. Although the field learned so much about the disease since the identification of the mutation in 2011, how the expanded repeat causes a particular type of fronto-temporal lobe dominant neurodegeneration and/or motor neuron degeneration is not yet clear. In this review, we summarize and discuss the current understandings of molecular mechanism of this repeat expansion mutation with focuses on the degradation and translation of the repeat containing RNA transcripts.
C9orf72 基因非编码区的六核苷酸重复扩展突变导致额颞叶痴呆和肌萎缩侧索硬化症。该突变估计是这些目前无法治愈的疾病最常见的遗传原因。由于突变导致常染色体显性遗传疾病，疾病级联本质上从扩展的 DNA 重复开始。然而，由于疾病的潜在毒性实体不仅是翻译的 C9ORF72 蛋白的功能丧失（如果有的话），而且还可能包括双向转录的含有扩展重复的 RNA 及其在所有可能的阅读框中的非常规重复相关的非 AUG 翻译产物，因此分子疾病机制不可避免地很复杂。尽管自 2011 年发现该突变以来，该领域对该疾病有了很多了解，但扩展重复如何导致特定类型的额颞叶优势神经退行性变和/或运动神经元退行性变尚不清楚。在这篇综述中，我们总结和讨论了目前对该重复扩展突变的分子机制的理解，重点是含有重复的 RNA 转录本的降解和翻译。
