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首页> 外文期刊>Cell and Tissue Research >C9orf72-associated neurodegeneration in ALS-FTD: breaking new ground in ribosomal RNA and nucleolar dysfunction
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C9orf72-associated neurodegeneration in ALS-FTD: breaking new ground in ribosomal RNA and nucleolar dysfunction

机译：Als-FTD中的C9ORF72相关神经变性：在核糖体RNA和核仁功能障碍中打破新的地面

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摘要

Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) are neurodegenerative diseases with distinct clinical appearance. However, both share as major genetic risk factor a C9orf72 locus intronic hexanucleotide expansion. The pathogenic pathways associated with the expansion-dependent neuronal toxicity are still poorly understood. Recent efforts to identify common threads of neuronal dysfunction have pointed towards deficits of ribosomal RNA (rRNA) biogenesis and loss of nucleolar integrity, a condition known as nucleolar stress that is an emerging shared feature among neurodegenerative diseases. Intriguingly, the C9orf72 mutation in ALS-FTD interferes with the function of the nucleolus by transcripts and dipeptide repeats (DPRs) produced by the hexanucleotide expansion. Experimental discrepancies have given rise to different hypotheses with regard to the connection of C9orf72 and nucleolar activity. In this review, we present and discuss emerging concepts concerning the impact of C9orf72 expansion on nucleolar biology. Moreover, we discuss the "nucleolar stress hypothesis," according to which nucleolar malfunction accompanies, exacerbates, or potentially triggers a degenerative phenotype. Upcoming awareness of the involvement of nucleolar stress in C9orf72 ALS-FTD could shed light into its pathogenesis, enabling potential treatment options aimed at shielding an "Achilles' heel" of neurons.
机译：肌萎缩侧面硬化症（ALS）和额颞造血退化（FTD）是具有明显临床外观的神经变性疾病。然而，两者都作为主要遗传危险因子A C9ORF72基因座内肾冬核核苷酸膨胀。与扩增依赖性神经元毒性相关的致病途径仍然很差。近期识别神经元功能障碍的常见线程的努力已经指出核糖体RNA（RRNA）生物发生和核仁完整性丧失的缺陷，其状况称为核仁应力，即神经变性疾病中的新出现共有特征。有趣的是，ALS-FTD中的C9ORF72突变干扰了通过己核苷酸膨胀产生的转录物和二肽重复（DPRS）的核仁的功能。实验差异在C9ORF72和核仁活性方面具有不同的假设。在本综述中，我们展示并讨论了关于C9ORF72扩张对核仁生物学影响的新兴概念。此外，我们讨论了“核仁应力假设”，根据该核肉发生故障伴随，加剧或潜在地触发退行性表型。即将到来，对核仁胁迫参与的认识在C9ORF72 ALS-FTD中可以脱光进入其发病机制，使潜在的治疗方案旨在屏蔽“阿基里斯”鞋跟的神经元。

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