Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Via L. De Crecchio 7, 80138 Naples, Italy.
Institute of Biostructures and Bioimaging (IBB), National Research Council (CNR), Via Mezzocannone 16, 80134 Napoli, Italy.
Int J Mol Sci. 2021 Dec 27;23(1):265. doi: 10.3390/ijms23010265.
The AIF/CypA complex exerts a lethal activity in several rodent models of acute brain injury. Upon formation, it translocates into the nucleus of cells receiving apoptotic stimuli, inducing chromatin condensation, DNA fragmentation, and cell death by a caspase-independent mechanism. Inhibition of this complex in a model of glutamate-induced cell death in HT-22 neuronal cells by an AIF peptide (AIF(370-394)) mimicking the binding site on CypA, restores cell survival and prevents brain injury in neonatal mice undergoing hypoxia-ischemia without apparent toxicity. Here, we explore the effects of the peptide on SH-SY5Y neuroblastoma cells stimulated with staurosporine (STS), a cellular model widely used to study Parkinson's disease (PD). This will pave the way to understanding the role of the complex and the potential therapeutic efficacy of inhibitors in PD. We find that AIF(370-394) confers resistance to STS-induced apoptosis in SH-SY5Y cells similar to that observed with CypA silencing and that the peptide works on the AIF/CypA translocation pathway and not on caspases activation. These findings suggest that the AIF/CypA complex is a promising target for developing novel therapeutic strategies against PD.
AIF/CypA 复合物在几种急性脑损伤的啮齿动物模型中发挥致命作用。形成后，它易位到接受凋亡刺激的细胞的细胞核中，通过 caspase 非依赖性机制诱导染色质浓缩、DNA 片段化和细胞死亡。在 HT-22 神经元细胞的谷氨酸诱导的细胞死亡模型中，用模拟 CypA 结合位点的 AIF 肽（AIF(370-394)）抑制该复合物，可恢复细胞存活并防止缺氧缺血的新生小鼠发生脑损伤，而没有明显的毒性。在这里，我们研究了该肽对用 staurosporine (STS)刺激的 SH-SY5Y 神经母细胞瘤细胞的影响，STS 是一种广泛用于研究帕金森病 (PD) 的细胞模型。这将为了解复合物的作用以及抑制剂在 PD 中的潜在治疗效果铺平道路。我们发现，AIF(370-394)使 SH-SY5Y 细胞对 STS 诱导的凋亡产生类似于 CypA 沉默观察到的抗性，并且该肽作用于 AIF/CypA 易位途径，而不是 caspase 激活。这些发现表明，AIF/CypA 复合物是开发针对 PD 的新型治疗策略的有前途的靶标。
