Percio Anna, Cicchinelli Michela, Masci Domiziana, Summo Mariagrazia, Urbani Andrea, Greco Viviana
Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
Department of Laboratory Diagnostic and Infectious Diseases, Unity of Chemistry, Biochemistry and Clinical Molecular Biology, Fondazione Policlinico Universitario Agostino Gemelli-IRCCS, 00168 Rome, Italy.
Antioxidants (Basel). 2024 Jul 23;13(8):883. doi: 10.3390/antiox13080883.
Redox dysregulation, an imbalance between oxidants and antioxidants, is crucial in the pathogenesis of various neurodegenerative diseases. Within this context, the "redoxome" encompasses the network of redox molecules collaborating to maintain cellular redox balance and signaling. Among these, cysteine-sensitive proteins are fundamental for this homeostasis. Due to their reactive thiol groups, cysteine (Cys) residues are particularly susceptible to oxidative post-translational modifications (PTMs) induced by free radicals (reactive oxygen, nitrogen, and sulfur species) which profoundly affect protein functions. Cys-PTMs, forming what is referred to as "cysteinet" in the redox proteome, are essential for redox signaling in both physiological and pathological conditions, including neurodegeneration. Such modifications significantly influence protein misfolding and aggregation, key hallmarks of neurodegenerative diseases such as Alzheimer's, Parkinson's, and notably, amyotrophic lateral sclerosis (ALS). This review aims to explore the complex landscape of cysteine PTMs in the cellular redox environment, elucidating their impact on neurodegeneration at protein level. By investigating specific cysteine-sensitive proteins and the regulatory networks involved, particular emphasis is placed on the link between redox dysregulation and ALS, highlighting this pathology as a prime example of a neurodegenerative disease wherein such redox dysregulation is a distinct hallmark.
氧化还原调节异常，即氧化剂与抗氧化剂之间的失衡，在各种神经退行性疾病的发病机制中起着关键作用。在此背景下，“氧化还原组”涵盖了协同维持细胞氧化还原平衡和信号传导的氧化还原分子网络。其中，对半胱氨酸敏感的蛋白质是这种体内平衡的基础。由于其反应性巯基，半胱氨酸（Cys）残基特别容易受到自由基（活性氧、氮和硫物种）诱导的氧化翻译后修饰（PTM）的影响，而这种修饰会深刻影响蛋白质功能。在氧化还原蛋白质组中形成所谓“半胱氨酸组”的半胱氨酸 - PTM，在生理和病理条件下，包括神经退行性变中，对氧化还原信号传导至关重要。这种修饰显著影响蛋白质错误折叠和聚集，而蛋白质错误折叠和聚集是阿尔茨海默病、帕金森病，尤其是肌萎缩侧索硬化症（ALS）等神经退行性疾病的关键特征。本综述旨在探索细胞氧化还原环境中半胱氨酸PTM的复杂情况，阐明它们在蛋白质水平对神经退行性变的影响。通过研究特定的半胱氨酸敏感蛋白质和相关的调节网络，特别强调氧化还原调节异常与ALS之间的联系，突出这种病理状况作为神经退行性疾病的一个主要例子，其中这种氧化还原调节异常是一个明显的标志。
