New insights of poly(ADP-ribosylation) in neurodegenerative diseases: A focus on protein phase separation and pathologic aggregation

Abnormal protein aggregation is a common pathological feature of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Protein posttranslational modifications (PTMs) play a crucial regulatory role in the formation of pathologic aggregation. Among the known PTMs involved in neurodegeneration, poly(ADP-ribosylation) (PARylation) has emerged with promising therapeutic potentials of the use of poly(ADP-ribose) (PAR) polymerase (PARP) inhibitors. In this review, we describe the mounting evidence that abnormal PARP activation is involved in various neurodegenerative diseases, and discuss the underpinning mechanisms with a focus on the recent findings that PARylation affects liquid-liquid phase separation and aggregation of amyloid proteins. We hope this review will stimulate further investigation of the unknown functions of PARylation and promote the development of more effective therapeutic agents in treating neurodegeneration.

异常蛋白质聚集是神经退行性疾病的常见病理特征，如阿尔茨海默病（AD）、帕金森病（PD）、亨廷顿病（HD）和肌萎缩侧索硬化症（ALS）。蛋白质翻译后修饰（PTMs）在病理性聚集的形成中起着关键的调节作用。在已知的与神经退行性变有关的翻译后修饰中，多聚（ADP - 核糖基化）（PARylation）随着多聚（ADP - 核糖）（PAR）聚合酶（PARP）抑制剂的使用展现出有前景的治疗潜力。在这篇综述中，我们描述了越来越多的证据表明异常的PARP激活与各种神经退行性疾病有关，并讨论了其基础机制，重点关注近期关于PARylation影响液 - 液相分离和淀粉样蛋白聚集的发现。我们希望这篇综述将激发对PARylation未知功能的进一步研究，并促进开发更有效的治疗神经退行性变的药物。