Genome instability and loss of protein homeostasis are hallmark events of age-related diseases that include neurodegeneration. Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis are characterized by protein aggregation, while an impaired DNA damage response (DDR) as in many genetic DNA repair disorders leads to pronounced neuropathological features. It remains unclear to what degree these cellular events interconnect with each other in the development of neurological diseases. This review highlights how the loss of protein homeostasis and genome instability influence one other. We will discuss studies that illustrate this connection. DNA damage contributes to many neurodegenerative diseases, as shown by an increased level of DNA damage in patients, possibly due to the effects of protein aggregates on chromatin, the sequestration of DNA repair proteins and novel putative DNA repair functions. Conversely, genome stability is also important for protein homeostasis. For example, gene copy number variations and the loss of key DDR components can lead to marked proteotoxic stress. An improved understanding of how protein homeostasis and genome stability are mechanistically connected is needed and promises to lead to the development of novel therapeutic interventions.

基因组不稳定性和蛋白质稳态丧失是包括神经退行性疾病在内的年龄相关疾病的标志性事件。一些神经退行性疾病，如阿尔茨海默病、帕金森病、亨廷顿病和肌萎缩性侧索硬化症，以蛋白质聚集为特征，而许多遗传 DNA 修复障碍中的受损 DNA 损伤反应 (DDR) 会导致明显的神经病理学特征。目前尚不清楚这些细胞事件在神经系统疾病发展过程中相互关联的程度。这篇综述强调了蛋白质稳态的丧失和基因组不稳定性如何相互影响。我们将讨论说明这种联系的研究。DNA 损伤会导致许多神经退行性疾病，如患者 DNA 损伤水平增加所示，可能是由于蛋白质聚集体对染色质、DNA 修复蛋白的隔离和新的假定 DNA 修复功能的影响。相反，基因组稳定性对于蛋白质稳态也很重要。例如，基因拷贝数变异和关键 DDR 成分的丢失会导致明显的蛋白质毒性压力。需要更好地理解蛋白质稳态和基因组稳定性如何在机械上相互关联，并有望导致开发新的治疗干预措施。