{"title":"调节性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","authors":"","doi":"10.1007/s00401-024-02722-0","DOIUrl":null,"url":null,"abstract":"<h3>Abstract</h3> <p>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.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3000,"publicationDate":"2024-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Regulated cell death and its role in Alzheimer’s disease and amyotrophic lateral sclerosis\",\"authors\":\"\",\"doi\":\"10.1007/s00401-024-02722-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3>Abstract</h3> <p>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. 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引用次数: 0
摘要
摘要 尽管开展了大量研究工作,但神经退行性疾病中神经细胞死亡的机制仍不明确。在过去的 20 年中,已经发现了多种可执行调控细胞死亡(RCD)的途径。在这些调节性细胞死亡途径中,细胞凋亡、坏死、热凋亡、铁凋亡、自噬相关细胞死亡和溶酶体依赖性细胞死亡得到了深入研究。虽然 RCD 由许多单独的途径组成,但已经发现了多种共同的蛋白质,可以从一种细胞死亡途径转移到另一种途径。内体机制等机制也增加了另一层复杂性,它们能够调节某些 RCD 途径的激活,防止细胞死亡。此外,RCD 激活还可能导致限制性轴突变性和突触修剪,而细胞体却不会丧失。RCD 在神经退行性病变过程中发挥着复杂的作用,在不同的疾病中表现各异。研究表明,RCD 在阿尔茨海默病(AD)和肌萎缩性脊髓侧索硬化症(ALS)这两种最常见的神经退行性疾病中的作用各不相同。在阿尔茨海默病中,神经元的丧失不仅与坏死的激活有关,而且还与热解的激活有关。而在 ALS 中,运动神经元的死亡与典型坏死无关,而在白质小胶质细胞中则可以看到热噬菌途径的激活。尽管 AD 和 ALS 在激活 RCD 通路方面存在这些差异,但对 p62/SQSTM1(序列组 1)免疫反应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的共同特征。在本综述中,我们将介绍在 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不同和相似参与。最后,我们将讨论针对 RCD 作为神经退行性疾病(如 AD 和 ALS)的创新治疗理念。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,因此通过靶向 RCD 防止患者神经元死亡似乎至关重要。这将为通过保持神经元活力来解决病理级联的上游事件提供宝贵的时间。
Regulated cell death and its role in Alzheimer’s disease and amyotrophic lateral sclerosis
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.
期刊介绍:
Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.