Mitroshina Elena V, Saviuk Mariia, Vedunova Maria V
Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhni Novgorod, Nizhny Novgorod, Russia.
Front Aging Neurosci. 2023 Jan 27;14:1016053. doi: 10.3389/fnagi.2022.1016053. eCollection 2022.
In the last few years, necroptosis, a recently described type of cell death, has been reported to play an important role in the development of various brain pathologies. Necroptosis is a cell death mechanism that has morphological characteristics similar to necrosis but is mediated by fundamentally different molecular pathways. Necroptosis is initiated by signaling through the interaction of RIP1/RIP3/MLKL proteins (receptor-interacting protein kinase 1/receptor-interacting protein kinase 3/mixed lineage kinase domain-like protein). RIPK1 kinase is usually inactive under physiological conditions. It is activated by stimulation of death receptors (TNFR1, TNFR2, TLR3, and 4, Fas-ligand) by external signals. Phosphorylation of RIPK1 results in the formation of its complex with death receptors. Further, complexes with the second member of the RIP3 and MLKL cascade appear, and the necroptosome is formed. There is enough evidence that necroptosis plays an important role in the pathogenesis of brain ischemia and neurodegenerative diseases. In recent years, a point of view that both neurons and glial cells can play a key role in the development of the central nervous system (CNS) pathologies finds more and more confirmation. Astrocytes play complex roles during neurodegeneration and ischemic brain damage initiating both impair and protective processes. However, the cellular and molecular mechanisms that induce pathogenic activity of astrocytes remain veiled. In this review, we consider these processes in terms of the initiation of necroptosis. On the other hand, it is important to remember that like other types of programmed cell death, necroptosis plays an important role for the organism, as it induces a strong immune response and is involved in the control of cancerogenesis. In this review, we provide an overview of the complex role of necroptosis as an important pathogenetic component of neuronal and astrocyte death in neurodegenerative diseases, epileptogenesis, and ischemic brain damage.
在过去几年中，坏死性凋亡作为一种最近被描述的细胞死亡类型，已被报道在各种脑部疾病的发展中起重要作用。坏死性凋亡是一种细胞死亡机制，其形态特征与坏死相似，但由根本不同的分子途径介导。坏死性凋亡通过RIP1/RIP3/MLKL蛋白（受体相互作用蛋白激酶1/受体相互作用蛋白激酶3/混合谱系激酶结构域样蛋白）的相互作用引发信号传导而启动。RIPK1激酶在生理条件下通常无活性。它通过外部信号刺激死亡受体（TNFR1、TNFR2、TLR3和4、Fas配体）而被激活。RIPK1的磷酸化导致其与死亡受体形成复合物。此外，与RIP3和MLKL级联反应的第二个成员形成复合物，坏死小体形成。有充分证据表明坏死性凋亡在脑缺血和神经退行性疾病发病机制中起重要作用。近年来，一种观点认为神经元和胶质细胞在中枢神经系统（CNS）疾病发展中都可发挥关键作用，这一观点得到越来越多的证实。星形胶质细胞在神经退行性变和缺血性脑损伤过程中发挥复杂作用，启动损伤和保护过程。然而，诱导星形胶质细胞致病活性的细胞和分子机制仍不清楚。在本综述中，我们从坏死性凋亡的启动角度考虑这些过程。另一方面，重要的是要记住，与其他类型的程序性细胞死亡一样，坏死性凋亡对机体也起重要作用，因为它会引发强烈的免疫反应并参与癌症发生的控制。在本综述中，我们概述了坏死性凋亡作为神经退行性疾病、癫痫发生和缺血性脑损伤中神经元和星形胶质细胞死亡的重要致病成分的复杂作用。
