MPP+ induces necrostatin-1- and ferrostatin-1-sensitive necrotic death of neuronal SH-SY5Y cells.
MPP+ induces necrostatin-1- and ferrostatin-1-sensitive necrotic death of neuronal SH-SY5Y cells.
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DOI：
10.1038/cddiscovery.2017.13
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发表时间：
2017
影响因子：
7
通讯作者：
Tsujimoto Y
中科院分区：
文献类型：
--
作者：
Ito K;Eguchi Y;Imagawa Y;Akai S;Mochizuki H;Tsujimoto Y
细胞死亡的调控是治疗神经退行性疾病等难治性疾病的一种有效方法。虽然已经有许多关于神经退行性疾病中可能涉及各种类型的细胞死亡的报道，但仍然不清楚这些疾病患者的神经元究竟是如何死亡的，因此尚未建立基于细胞死亡调节的治疗策略。为了深入了解神经退行性疾病中细胞死亡的机制，我们研究了1-甲基-4-苯基吡啶（MPP+）对人神经母细胞瘤细胞系SH-SY 5 Y（一种广泛使用的帕金森病模型）的影响。我们发现MPP+主要诱导神经元分化的SH-SY 5 Y细胞的非凋亡性死亡。这种细胞死亡被坏死性凋亡抑制剂necrostatin-1（Nec-1）和含吲哚化合物（3，3 ′-二吲哚甲烷：DIM）强烈抑制。然而，它的发生独立于受体相互作用丝氨酸/苏氨酸蛋白激酶1/3（RIP 1/RIP 3），表明这种形式的细胞死亡不是坏死性凋亡。MPP+诱导的细胞死亡也受到几种铁凋亡抑制剂的抑制，包括ferrostatin-1（Fer-1）。虽然MPP+诱导的死亡和铁凋亡有一些共同的特征，如脂质过氧化的发生和Fer-1的抑制，但MPP+诱导的死亡似乎与铁凋亡不同，因为MPP+诱导的死亡（而不是铁凋亡）被Nec-1抑制，不依赖于p53，并伴有ATP耗竭和线粒体肿胀。MPP+诱导的非凋亡性细胞死亡的进一步研究可能有助于了解神经元损失的机制和治疗神经退行性疾病，如帕金森病。
Regulation of cell death is potentially a powerful treatment modality for intractable diseases such as neurodegenerative diseases. Although there have been many reports about the possible involvement of various types of cell death in neurodegenerative diseases, it is still unclear exactly how neurons die in patients with these diseases, thus treatment strategies based on cell death regulation have not been established yet. To obtain some insight into the mechanisms of cell death involved in neurodegenerative diseases, we studied the effect of 1-methyl-4-phenylpyridinium (MPP+) on the human neuroblastoma cell line SH-SY5Y (a widely used model of Parkinson’s disease). We found that MPP+ predominantly induced non-apoptotic death of neuronally differentiated SH-SY5Y cells. This cell death was strongly inhibited by necrostatin-1 (Nec-1), a necroptosis inhibitor, and by an indole-containing compound (3,3′-diindolylmethane: DIM). However, it occurred independently of receptor-interacting serine/threonine-protein kinase 1/3 (RIP1/RIP3), indicating that this form of cell death was not necroptosis. MPP+-induced cell death was also inhibited by several inhibitors of ferroptosis, including ferrostatin-1 (Fer-1). Although MPP+-induced death and ferroptosis shared some features, such as occurrence of lipid peroxidation and inhibition by Fer-1, MPP+-induced death seemed to be distinct from ferroptosis because MPP+-induced death (but not ferroptosis) was inhibited by Nec-1, was independent of p53, and was accompanied by ATP depletion and mitochondrial swelling. Further investigation of MPP+-induced non-apoptotic cell death may be useful for understanding the mechanisms of neuronal loss and for treatment of neurodegenerative diseases such as Parkinson’s disease.