In 2011, a hexanucleotide repeat expansion (HRE) in the noncoding region of C9orf72 was associated with the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The main pathogenic mechanisms in C9-ALS/FTD are haploinsufficiency of the C9orf72 protein and gain of function toxicity from bidirectionally-transcribed repeat-containing RNAs and dipeptide repeat proteins (DPRs) resulting from non-canonical RNA translation. Additionally, abnormalities in different downstream cellular mechanisms, such as nucleocytoplasmic transport and autophagy, play a role in pathogenesis. Substantial research efforts using in vitro and in vivo models have provided valuable insights into the contribution of each mechanism in disease pathogenesis. However, conflicting evidence exists, and a unifying theory still lacks.

Here, we provide an overview of the recently published literature on clinical, neuropathological and molecular features of C9-ALS/FTD. We highlight the supposed neuronal role of C9orf72 and the HRE pathogenic cascade, mainly focusing on the contribution of RNA foci and DPRs to neurodegeneration and discussing the several downstream mechanisms. We summarize the emerging biochemical and neuroimaging biomarkers, as well as the potential therapeutic approaches. Despite promising results, a specific disease-modifying treatment is still not available to date and greater insights into disease mechanisms may help in this direction.

2011年，C9orf72非编码区的六核苷酸重复扩增（HRE）与额颞叶痴呆（FTD）和肌萎缩性侧索硬化（ALS）的最常见遗传原因相关。C9-ALS / FTD的主要致病机制是C9orf72蛋白的单倍不足，以及双向转录的含重复RNA和非规范RNA翻译产生的二肽重复蛋白（DPR）引起的功能毒性。另外，在不同的下游细胞机制中的异常，例如核质运输和自噬，在发病机理中起作用。大量的研究工作，利用体外和体内这些模型为了解每种机制在疾病发病机理中的作用提供了宝贵的见识。但是，存在矛盾的证据，仍然缺乏统一的理论。

在这里，我们提供有关C9-ALS / FTD的临床，神经病理学和分子特征的最新出版文献的概述。我们重点介绍了C9orf72和HRE病原级联反应的神经元作用，主要侧重于RNA病灶和DPR对神经变性的贡献，并讨论了几种下游机制。我们总结了新兴的生化和神经影像生物标志物，以及潜在的治疗方法。尽管取得了令人鼓舞的结果，但迄今为止尚无一种特定的疾病缓解疗法，对疾病机制的更深入了解可能会朝这个方向提供帮助。