Maintaining genomic stability constitutes a major challenge facing cells. DNA breaks can arise from direct oxidative damage to the DNA backbone, the inappropriate activities of endogenous enzymes such as DNA topoisomerases, or due to transcriptionally-derived RNA/DNA hybrids (R-loops). The progressive accumulation of DNA breaks has been linked to several neurological disorders. Recently, however, several independent studies have implicated nuclear and mitochondrial genomic instability, perturbed co-transcriptional processing, and impaired cellular clearance pathways as causal and intertwined mechanisms underpinning neurodegeneration. Here, we discuss this emerging paradigm in the context of amyotrophic lateral sclerosis and frontotemporal dementia, and outline how this knowledge paves the way to novel therapeutic interventions.

中文翻译：

---

受干扰的自噬和 DNA 修复共同促进肌萎缩侧索硬化症和痴呆症的神经退行性变

维持基因组稳定性是细胞面临的主要挑战。DNA 断裂可能是由于 DNA 主链的直接氧化损伤、内源酶（例如 DNA 拓扑异构酶）的不当活性或转录衍生的 RNA/DNA 杂合体（R 环）引起的。DNA 断裂的逐渐积累与多种神经系统疾病有关。然而，最近的几项独立研究表明，核和线粒体基因组不稳定性、共转录处理受到干扰以及细胞清除途径受损是神经退行性变的因果和相互交织的机制。在这里，我们在肌萎缩侧索硬化症和额颞叶痴呆的背景下讨论这一新兴范例，并概述这些知识如何为新型治疗干预措施铺平道路。