FOXO and related transcription factors binding elements in the regulation of neurodegenerative disorders
FOXO and related transcription factors binding elements in the regulation of neurodegenerative disorders
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DOI：
10.1016/j.jchemneu.2021.102012
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发表时间：
2021-08-17
影响因子：
2.8
通讯作者：
Kumar, Pravir
中科院分区：
文献类型：
--
作者：
Oli, Vaibhav;Gupta, Rohan;Kumar, Pravir
神经退行性疾病，如阿尔茨海默病、帕金森病、亨廷顿病、肌萎缩侧索硬化症等，其特征是神经元细胞进行性丧失，从而导致记忆障碍和认知能力下降。越来越多的证据证明了不同生物过程的可能影响，即氧化应激、线粒体功能障碍、异常细胞周期重入、翻译后修饰、蛋白质聚集、蛋白酶体功能障碍、自噬以及许多其他导致神经元细胞死亡的过程。由于此类疾病发病机制和机制复杂，目前尚无有效治疗方法，病情日益恶化。越来越多的证据证明了调节转录因子的作用，例如 NF kappa beta、FoxO、Myc、CREB 和其他调节生物过程并减少疾病进展和发病机制的因子。研究表明叉头框 O (FoxO) 转录因子与衰老和长寿的调节有关。此外，FoxO 蛋白的功能受到不同翻译后修饰 (PTM) 的调节，即乙酰化和泛素化。各种研究得出结论，FoxO 蛋白发挥神经保护和神经毒性特性，具体取决于它们在大脑中的调节机制和活动。因此，了解 FoxO 在大脑中表达和活动的本质将有助于制定有效的治疗策略。在此，我们首先讨论FoxO蛋白在细胞周期调节和细胞增殖中的作用，然后讨论FoxO蛋白通过乙酰化和泛素化的调节。我们还简要解释了 FoxO 蛋白在神经元细胞中的活性和表达模式，并解释了 FoxO 蛋白从氧化应激诱导的神经毒性中解救的机制。随后，我们详细介绍了 FoxO 蛋白在神经退行性疾病中的影响以及 FoxO 蛋白作为有效的治疗靶点。
Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and others, are characterized by progressive loss of neuronal cells, which causes memory impairment and cognitive decline. Mounting evidence demonstrated the possible implications of diverse biological processes, namely oxidative stress, mitochondrial dysfunction, aberrant cell cycle re-entry, post-translational modifications, protein aggregation, impaired proteasome dysfunction, autophagy, and many others that cause neuronal cell death. The condition worsens as there is no effective treatment for such diseases due to their complex pathogenesis and mechanism. Mounting evidence demonstrated the role of regulatory transcription factors, such as NF kappa beta, FoxO, Myc, CREB, and others that regulate the biological processes and diminish the disease progression and pathogenesis. Studies demonstrated that forkhead box O (FoxO) transcription factors had been implicated in the regulation of aging and longevity. Further, the functions of FoxO proteins are regulated by different post-translational modifications (PTMs), namely acetylation, and ubiquitination. Various studies concluded that FoxO proteins exert both neuroprotective and neurotoxic properties depending on their regulation mechanism and activity in the brain. Thus, understanding the nature of FoxO expression and activity in the brain will help develop effective therapeutic strategies. Herein, firstly, we discuss the role of FoxO protein in cell cycle regulation and cell proliferation, followed by the regulation of FoxO proteins through acetylation and ubiquitination. We also briefly explain the activity and expression pattern of FoxO proteins in the neuronal cells and explain the mechanism through which FoxO proteins are rescued from oxidative stress-induced neurotoxicity. Later on, we present a detailed view of the implication of FoxO proteins in neurodegenerative disease and FoxO proteins as an effective therapeutic target.