The complexity of neurodegeneration restricts the ability to understand and treat the neurological disorders affecting millions of people worldwide. Therefore, there is an unmet need to develop new and more effective therapeutic strategies to combat these devastating conditions and that will only be achieved with a better understanding of the biological mechanism associated with disease conditions. Recent studies highlight the role of DNA damage, particularly, DNA double-strand breaks (DSBs), in the progression of neuronal loss in a broad spectrum of human neurodegenerative diseases. This is not unexpected because neurons are prone to DNA damage due to their non-proliferative nature and high metabolic activity. However, it is not clear if DSBs is a primary driver of neuronal loss in disease conditions or simply occurs concomitant with disease progression. Here, we provide evidence that supports a critical role of DSBs in the pathogenesis of the neurodegenerative diseases. Among different kinds of DNA damages, DSBs are the most harmful and perilous type of DNA damage and can lead to cell death if left unrepaired or repaired with error. In this review, we explore the current state of knowledge regarding the role of DSBs repair mechanisms in preserving neuronal function and survival and describe how DSBs could drive the molecular mechanisms resulting in neuronal death in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We also discuss the potential implications of DSBs as a novel therapeutic target and prognostic marker in patients with neurodegenerative conditions.

中文翻译：

---

DNA 双链断裂：神经退行性疾病的潜在治疗靶点。


神经退行性疾病的复杂性限制了理解和治疗影响全世界数百万人的神经系统疾病的能力。因此，开发新的、更有效的治疗策略来对抗这些破坏性病症的需求尚未得到满足，而这只有通过更好地了解与疾病相关的生物学机制才能实现。最近的研究强调了 DNA 损伤，特别是 DNA 双链断裂 (DSB) 在人类神经退行性疾病中神经元损失进展中的作用。这并不意外，因为神经元由于其非增殖性质和高代谢活性而容易受到 DNA 损伤。然而，尚不清楚 DSB 是否是疾病状态下神经元损失的主要驱动因素，或者只是伴随疾病进展而发生。在这里，我们提供的证据支持 DSB 在神经退行性疾病发病机制中的关键作用。在不同类型的 DNA 损伤中，DSB 是最有害和最危险的 DNA 损伤类型，如果不修复或修复错误，可能会导致细胞死亡。在这篇综述中，我们探讨了目前关于 DSB 修复机制在保护神经元功能和存活方面的作用的知识状况，并描述了 DSB 如何驱动导致神经退行性疾病（如阿尔茨海默病、帕金森病和肌萎缩症）中神经元死亡的分子机制。侧索硬化。我们还讨论了 DSB 作为神经退行性疾病患者的新治疗靶点和预后标志物的潜在影响。