Laboratory for Neuropathology, Department of Imaging and Pathology and Leuven Brain Institute (LBI), KU-Leuven, Herestraat 49, 3000, Leuven, Belgium.
Department of Pathology, University Hospitals Leuven, Leuven, Belgium.
Acta Neuropathol. 2024 Apr 7;147(1):69. doi: 10.1007/s00401-024-02722-0.
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.
尽管已经进行了大量的研究，但神经元细胞在神经退行性疾病中死亡的机制仍不清楚。在过去的 20 年中，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，凋亡、坏死性凋亡、细胞焦亡、铁死亡、自噬相关细胞死亡和溶酶体依赖性细胞死亡已被深入研究。尽管 RCD 由许多单独的途径组成，但已经确定了许多共同的蛋白质，这些蛋白质允许从一种细胞死亡途径转变为另一种途径。内体机制等另一个层面的复杂性增加了，这些机制能够调节一些 RCD 途径的激活，从而防止细胞死亡。此外，由于 RCD 的激活，轴突受限的退化和突触修剪也可能发生，而不会导致细胞体丢失。RCD 在神经退行性过程中发挥着复杂的作用，在不同的疾病中表现不同。已经表明，RCD 在最常见的神经退行性疾病阿尔茨海默病 (AD) 和肌萎缩侧索硬化症 (ALS) 中存在差异。在 AD 中，神经元的丢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，运动神经元的死亡与经典的坏死性凋亡无关，而细胞焦亡途径的激活则见于白质小胶质细胞中。尽管在 AD 和 ALS 中 RCD 途径的激活存在差异，但对 p62/SQSTM1（自噬体 1）免疫反应性蛋白聚集体的积累是这两种疾病和许多其他神经退行性疾病的共同事件。在这篇综述中，我们描述了在 AD 和 ALS 中明确激活的主要 RCD 途径，这些途径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 的执行或“细胞自杀”代表了神经退行性变的最后阶段，通过靶向 RCD 防止神经元死亡对患者来说似乎至关重要。这将通过保持神经元存活来为解决病理级联反应中的上游事件提供宝贵的时间。
