Abstract

Despite considerable research efforts, it is still not clear which mechanisms underlie neuronal cell death in neurodegenerative diseases. During the last 20 years, multiple pathways have been identified that can execute regulated cell death (RCD). Among these RCD pathways, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-related cell death, and lysosome-dependent cell death have been intensively investigated. Although RCD consists of numerous individual pathways, multiple common proteins have been identified that allow shifting from one cell death pathway to another. Another layer of complexity is added by mechanisms such as the endosomal machinery, able to regulate the activation of some RCD pathways, preventing cell death. In addition, restricted axonal degeneration and synaptic pruning can occur as a result of RCD activation without loss of the cell body. RCD plays a complex role in neurodegenerative processes, varying across different disorders. It has been shown that RCD is differentially involved in Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), among the most common neurodegenerative diseases. In AD, neuronal loss is associated with the activation of not only necroptosis, but also pyroptosis. In ALS, on the other hand, motor neuron death is not linked to canonical necroptosis, whereas pyroptosis pathway activation is seen in white matter microglia. Despite these differences in the activation of RCD pathways in AD and ALS, the accumulation of protein aggregates immunoreactive for p62/SQSTM1 (sequestosome 1) is a common event in both diseases and many other neurodegenerative disorders. In this review, we describe the major RCD pathways with clear activation in AD and ALS, the main interactions between these pathways, as well as their differential and similar involvement in these disorders. Finally, we will discuss targeting RCD as an innovative therapeutic concept for neurodegenerative diseases, such as AD and ALS. Considering that the execution of RCD or “cellular suicide” represents the final stage in neurodegeneration, it seems crucial to prevent neuronal death in patients by targeting RCD. This would offer valuable time to address upstream events in the pathological cascade by keeping the neurons alive.

中文翻译：

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调节细胞死亡及其在阿尔茨海默病和肌萎缩侧索硬化症中的作用

摘要

尽管进行了大量的研究工作，但仍不清楚神经退行性疾病中神经元细胞死亡的机制是什么。在过去的 20 年里，已经确定了多种可以执行调节性细胞死亡 (RCD) 的途径。在这些 RCD 途径中，细胞凋亡、坏死性凋亡、细胞焦亡、铁死亡、自噬相关的细胞死亡和溶酶体依赖性细胞死亡已得到深入研究。尽管 RCD 由许多单独的途径组成，但已发现多种常见蛋白质可以从一种细胞死亡途径转变为另一种细胞死亡途径。内体机制等机制增加了另一层复杂性，能够调节一些 RCD 途径的激活，防止细胞死亡。此外，RCD 激活可导致有限的轴突变性和突触修剪，而不会损失细胞体。 RCD 在神经退行性过程中发挥着复杂的作用，不同疾病的作用各不相同。研究表明，RCD 与阿尔茨海默病 (AD) 和肌萎缩侧索硬化症 (ALS) 等最常见的神经退行性疾病有不同程度的相关性。在 AD 中，神经元损失不仅与坏死性凋亡的激活有关，还与细胞焦亡的激活有关。另一方面，在 ALS 中，运动神经元死亡与典型的坏死性凋亡无关，而焦亡途径激活则在白质小胶质细胞中可见。尽管 AD 和 ALS 中 RCD 通路的激活存在这些差异，但对 p62/SQSTM1（隔离体 1）具有免疫反应性的蛋白质聚集体的积累是这两种疾病和许多其他神经退行性疾病中的常见事件。在这篇综述中，我们描述了 AD 和 ALS 中明显激活的主要 RCD 通路、这些通路之间的主要相互作用，以及它们在这些疾病中的差异和相似参与。最后，我们将讨论将 RCD 作为治疗 AD 和 ALS 等神经退行性疾病的创新治疗概念。考虑到 RCD 或“细胞自杀”的执行代表了神经退行性变的最后阶段，通过针对 RCD 来预防患者神经元死亡似乎至关重要。这将为通过保持神经元存活来解决病理级联中的上游事件提供宝贵的时间。