Mansour Heba M, Mohamed Ahmed F, El-Khatib Aiman S, Khattab Mahmoud M
Egyptian Drug Authority, EDA, Giza, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Ageing Res Rev. 2023 Mar;85:101841. doi: 10.1016/j.arr.2022.101841. Epub 2023 Jan 3.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the world. Motor impairment seen in PD is associated with dopaminergic neurotoxicity in the striatum, and dopaminergic neuronal death in the substantia nigra pars compacta. Cell death has a significant effect on the development and progression of PD. Extensive research over the last few decades has unveiled new regulated cell death (RCD) mechanisms that are not dependent on apoptosis such as necroptosis, ferroptosis, and others. In this review, we will overview the mechanistic pathways of different types of RCD. Unlike accidental cell death, RCD subroutines can be regulated and the RCD-associated kinases are potential druggable targets. Hence, we will address an overview and analysis of different kinases regulating apoptosis such as receptor-interacting protein kinase 1 (RIPK-1), RIPK3, mixed lineage kinase (MLK), Ataxia telangiectasia muted (ATM), cyclin-dependent kinase (CDK), death-associated protein kinase 1 (DAPK1), Apoptosis-signaling kinase-1 (ASK-1), and Leucine-rich repeat kinase-2 (LRRK2). In addition to the role of RIPK1, RIPK3, and Mixed Lineage Kinase Domain like Pseudokinase (MLKL) in necroptosis. We also overview functions of AMP-kinase (AMPK), protein kinase C (PKC), RIPK3, and ATM in ferroptosis. We will recap the anti-apoptotic, anti-necroptotic, and anti-ferroptotic effects of different kinase inhibitors in different models of PD. Finally, we will discuss future challenges in the repositioning of kinase inhibitors in PD. In conclusion, this review kicks-start targeting RCD from a kinases perspective, opening novel therapeutic disease-modifying therapeutic avenues for PD.
帕金森病（PD）是世界上第二常见的神经退行性疾病。PD中出现的运动障碍与纹状体中的多巴胺能神经毒性以及黑质致密部中的多巴胺能神经元死亡有关。细胞死亡对PD的发生和发展有重大影响。在过去几十年中，广泛的研究揭示了新的程序性细胞死亡（RCD）机制，这些机制不依赖于细胞凋亡，如坏死性凋亡、铁死亡等。在本综述中，我们将概述不同类型RCD的机制途径。与意外细胞死亡不同，RCD子程序可以被调节，并且与RCD相关的激酶是潜在的可成药靶点。因此，我们将概述和分析调节细胞凋亡的不同激酶，如受体相互作用蛋白激酶1（RIPK-1）、RIPK3、混合谱系激酶（MLK）、共济失调毛细血管扩张症突变基因（ATM）、细胞周期蛋白依赖性激酶（CDK）、死亡相关蛋白激酶1（DAPK1）、凋亡信号激酶-1（ASK-1）和富含亮氨酸重复激酶-2（LRRK2）。除了RIPK1、RIPK3和混合谱系激酶结构域样假激酶（MLKL）在坏死性凋亡中的作用外。我们还概述了AMP激酶（AMPK）、蛋白激酶C（PKC）、RIPK3和ATM在铁死亡中的功能。我们将回顾不同激酶抑制剂在不同PD模型中的抗凋亡、抗坏死性凋亡和抗铁死亡作用。最后，我们将讨论激酶抑制剂在PD重新定位方面未来面临的挑战。总之，本综述从激酶的角度开启了针对RCD的研究，为PD开辟了新的疾病修饰治疗途径。
