Department of Pharmacology, School of Pharmaceutical Education and Research, SPER Jamia Hamdard, New Delhi 110062, India.
Department of Pharmaceutics, School of Pharmaceutical Education and Research, SPER Jamia Hamdard, New Delhi 110062, India.
CNS Neurol Disord Drug Targets. 2021;20(1):54-67. doi: 10.2174/1871527319666200903162200.
Neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Huntington's Disease (HD), are characterized by progressive neuronal dysfunction and death. Recent studies have established detrimental modifications in the structure and function of brain proteins, which stimulate their aggregation, misfolding and deposition in and around the neurons an important hallmark of neurodegenerative diseases. Post-Translational Modification (PTM) of proteins, including phosphorylation, acetylation, glycosylation, palmitoylation, SUMOylation, and ubiquitination, are important regulators of protein characteristics, including stability, intracellular distribution, activity, interactions, aggregation and clearance. Despite clear evidence that altered protein modifications emerging from impromptu chemical modifications to side chains of amino acid are associated with neurodegeneration, the underlying mechanisms that promote aberrant PTM remain poorly understood. Therefore, elucidating PTM of specific disease-associated proteins can prove to be a significant step in evaluating the functional alteration of proteins and their association with neurodegeneration. This review describes how aberrant PTM of various proteins is linked with the neurodegenerative disease pathogenesis, as well as molecular strategies targeting these modifications for treating such diseases, which are yet incurable.
神经退行性疾病包括阿尔茨海默病（AD）、帕金森病（PD）、肌萎缩侧索硬化症（ALS）和亨廷顿病（HD），其特征是神经元功能进行性障碍和死亡。最近的研究已经确定了大脑蛋白质结构和功能的有害变化，这些变化会刺激它们在神经元内外聚集、错误折叠和沉积，这是神经退行性疾病的一个重要标志。蛋白质的翻译后修饰（PTM），包括磷酸化、乙酰化、糖基化、棕榈酰化、SUMO 化和泛素化，是蛋白质特性的重要调节剂，包括稳定性、细胞内分布、活性、相互作用、聚集和清除。尽管有明确的证据表明，氨基酸侧链上自发的化学修饰导致的蛋白质修饰改变与神经退行性变有关，但促进异常 PTM 的潜在机制仍知之甚少。因此，阐明特定与疾病相关的蛋白质的 PTM 可以被证明是评估蛋白质功能改变及其与神经退行性变关联的重要步骤。本文综述了各种蛋白质的异常 PTM 如何与神经退行性疾病发病机制相关，以及针对这些修饰的分子策略如何治疗目前仍无法治愈的此类疾病。
