Hexanucleotide repeat expansions represent the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which such expansions cause neurodegeneration are poorly understood. We report elevated levels of DNA-RNA hybrids (R-loops) and double strand breaks in rat neurons, human cells and C9orf72 ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated DNA repair signaling and accumulation of protein-linked DNA breaks. We reveal that defective ATM-mediated DNA repair is a consequence of P62 accumulation, which impairs H2A ubiquitylation and perturbs ATM signaling. Virus-mediated expression of C9orf72-related RNA and dipeptide repeats in the mouse central nervous system increases double strand breaks and ATM defects and triggers neurodegeneration. These findings identify R-loops, double strand breaks and defective ATM-mediated repair as pathological consequences of C9orf72 expansions and suggest that C9orf72-linked neurodegeneration is driven at least partly by genomic instability.

中文翻译：

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C9orf72 扩增破坏了 ATM 介导的染色体断裂修复。

六核苷酸重复扩增是肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆最常见的遗传原因，但人们对这种扩增导致神经退行性变的机制知之甚少。我们报告大鼠神经元、人类细胞和 C9orf72 ALS 患者脊髓组织中 DNA-RNA 杂合体（R 环）和双链断裂水平升高。内源性 DNA 损伤的积累伴随有缺陷的 ATM 介导的 DNA 修复信号和蛋白质相关 DNA 断裂的积累。我们揭示了 ATM 介导的 DNA 修复缺陷是 P62 积累的结果，这会损害 H2A 泛素化并扰乱 ATM 信号传导。小鼠中枢神经系统中 C9orf72 相关 RNA 和二肽重复序列的病毒介导表达增加了双链断裂和 ATM 缺陷并引发神经变性。这些发现将 R 环、双链断裂和 ATM 介导的修复缺陷确定为 C9orf72 扩增的病理后果，并表明 C9orf72 相关的神经变性至少部分是由基因组不稳定性驱动的。