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Molecular mechanisms of cell death in neurological diseases
Cell Death and Differentiation ( IF 12.4 ) Pub Date : 2021-06-07 , DOI: 10.1038/s41418-021-00814-y
Diane Moujalled 1, 2 , Andreas Strasser 1, 2 , Jeffrey R Liddell 3
Affiliation  

Tightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.



中文翻译:

神经系统疾病中细胞死亡的分子机制

紧密协调的程序性细胞死亡 (PCD) 信号事件在正常神经元发育过程中以空间和时间限制的方式发生,以建立神经结构和塑造 CNS。在各种神经系统疾病的发病机制中可以观察到 PCD 信号级联的异常,例如与自噬相关的细胞凋亡、坏死性凋亡、细胞焦亡、铁死亡和细胞死亡以及非程序性坏死。这些细胞死亡可以响应于各种形式的细胞应激(由细胞内或细胞外刺激施加)和炎症过程而被激活。PCD 通路的异常激活是神经退行性疾病的常见特征,例如肌萎缩侧索硬化症 (ALS)、阿尔茨海默病、帕金森病和亨廷顿病,导致不必要的神经元细胞和功能丧失。相反,PCD 的失活被认为有助于脑癌的发展并影响其对治疗的反应。对于许多神经退行性疾病和脑癌,目前的治疗策略效果不佳,因此需要对这些疾病的起源进行调查。由于许多脑部疾病在 PCD 通路中表现出异常,看来可以抑制或诱导 PCD 的药物可能是未来治疗策略的关键组成部分。此类疗法的开发必须以忠实模仿人类疾病的动物模型的临床前研究为指导。在本次审查中,我们简要描述了 PCD 和未程序化的细胞死亡过程,以及它们在导致大脑中的神经退行性疾病或肿瘤发生中所起的作用。我们还讨论了不同的细胞死亡信号级联和疾病发病机制之间的相互作用,并描述了针对已进入临床试验的细胞死亡信号通路中的关键参与者的药物。

更新日期:2021-06-08
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