Sulthana Nasreen, Mittal Piyush, Goyal Ahsas, Ballal Suhas, Maharana Laxmidhar, Rana Amita Joshi, Khan Yumna, Goyal Kavita, Mishra Rakhi, Ali Haider, Gupta Gaurav, Hussain Md Sadique
Department of Pharmacology, Sree Dattha Institute of Pharmacy, Sheriguda, Hyderabad, Telangana, 501510, India.
Department of Pharmacy Practice, Teerthanker Mahaveer of College of Pharmacy, Teerthanker Mahaveer University, Moradabad, India.
Apoptosis. 2025 Jul 23. doi: 10.1007/s10495-025-02148-3.
Apoptosis signal-regulating kinase 1 (ASK1), a redox-sensitive member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, is a master regulator of neuronal apoptosis as well as neuroinflammation in neurodegenerative disorders (NDs). Under oxidative and endoplasmic reticulum stress conditions, ASK1 sets off a series of pathways, ultimately leading to impairment of cellular functions and the cell's demise. The comprehensive review focuses on the diverse contributions of ASK1 to neurodegeneration driven by Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Human and animal evidence links dysregulated ASK1 signaling is related to amyloid deposition, tau hyperphosphorylation, neuroinflammation, abnormal protein folding, and subsequent neurodegeneration. ASK1 plays a role in tau hyperphosphorylation and amyloid-beta-induced neurotoxicity in AD. ASK1-mediated apoptosis of dopaminergic neurons caused by oxidative stress and aggregation of α-synuclein contributes to PD. Furthermore, ASK1 activation is associated with motor neuron degeneration in ALS related to endoplasmic reticulum stress caused by mutant SOD1. Moreover, the pathogenesis of HD involves the activation of ASK1 by the cellular stress caused by mutant huntingtin protein. ASK1 signaling potentiates inflammatory signals in MS because it is involved in demyelination and neuronal injury. Nonetheless, obstacles persist such as developing brain-targeted therapies, reducing adverse systemic effects, and defining disease-stage-specific functions of ASK1. This review aims to comprehensively examine the role of ASK1 signaling in major NDs, discuss its upstream and downstream regulatory mechanisms, and evaluate the current and emerging therapeutic strategies targeting ASK1.
凋亡信号调节激酶1（ASK1）是丝裂原活化蛋白激酶激酶激酶（MAP3K）家族中对氧化还原敏感的成员，是神经退行性疾病（NDs）中神经元凋亡以及神经炎症的主要调节因子。在氧化应激和内质网应激条件下，ASK1引发一系列信号通路，最终导致细胞功能受损和细胞死亡。这篇综述聚焦于ASK1在由阿尔茨海默病（AD）、帕金森病（PD）、亨廷顿病（HD）、肌萎缩侧索硬化症（ALS）和多发性硬化症（MS）引发的神经退行性变中的多种作用。人和动物研究证据表明，ASK1信号失调与淀粉样蛋白沉积、tau蛋白过度磷酸化、神经炎症、异常蛋白质折叠以及随后的神经退行性变有关。ASK1在AD的tau蛋白过度磷酸化和β淀粉样蛋白诱导的神经毒性中起作用。ASK1介导的由氧化应激和α-突触核蛋白聚集引起的多巴胺能神经元凋亡导致PD。此外，ASK1激活与ALS中与突变型超氧化物歧化酶1（SOD1）引起的内质网应激相关的运动神经元变性有关。此外，HD的发病机制涉及突变型亨廷顿蛋白引起的细胞应激激活ASK1。ASK1信号增强MS中的炎症信号，因为它参与脱髓鞘和神经元损伤。尽管如此，仍然存在障碍，如开发针对大脑的疗法、减少不良全身效应以及确定ASK1在疾病阶段特异性的功能。这篇综述旨在全面研究ASK1信号在主要NDs中的作用，讨论其上游和下游调节机制，并评估针对ASK1的现有和新兴治疗策略。
