Relevance of AIF/CypA Lethal Pathway in SH-SY5Y Cells Treated with Staurosporine

Abstract

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.

Relationships Between Rapid Eye Movement Sleep Behavior Disorder and Parkinson’s Disease: Indication from Gut Microbiota Alterations

“…For the functional prediction, the overlapping pathway, enriched staurosporine biosynthesis in iRBD and PD with RBD, also supported the similarity between iRBD and PD. SH-SY5Y neuroblastoma cells stimulated with staurosporine is regarded as a classic cellular widely used to study Parkinson's disease 31 , the increase of staurosporine biosynthesis observed in our study might indicate the toxicity of staurosporine would active pathogenic autophagy with respect to dopaminergic cell loss 32 , resulting in the pathogenesis of RBD and PD.…”

Relationships Between Rapid Eye Movement Sleep Behavior Disorder and Parkinson’s Disease: Indication from Gut Microbiota Alterations

“…For the functional prediction, the overlapping pathway, enriched staurosporine biosynthesis in iRBD and PD with RBD, also supported the similarity between iRBD and PD. Staurosporine stimulated SH-SY5Y neuroblastoma cells are regarded as a classic cellular model widely used in studying PD [ 58 ], the increase of staurosporine biosynthesis observed in our study might indicate the toxicity of staurosporine would active pathogenic autophagy with respect to dopaminergic cell loss [ 59 ], resulting in the pathogenesis of RBD and PD.…”

Autophagy inhibitors 3‐MA and BAF may attenuate hippocampal neuronal necroptosis after global cerebral ischemia–reperfusion injury in male rats by inhibiting the interaction of the RIP3/AIF/CypA complex

“…The AIF/H2AX/CypA complex leads to chromatin condensation, DNA fragmentation, and chromatinolysis, which ultimately leads to cell death (Rodriguez et al., 2021). This complex is involved in various types of brain injury, such as cerebral hypoxia‐ischemia, stroke, and traumatic brain injury (Conte et al., 2021; Piao et al., 2012; Rodriguez et al., 2020).…”

“…After cerebral ischemia and hypoxia, AIF and CypA combined with each other in the neurons; AIF and CypA cannot enter the nucleus without the other one (Zhu et al., 2007). The interaction of CypA with AIF is also involved in other injury types, such as neonatal brain hypoxia‐ischemia (HI) injury (Rodriguez et al., 2020), Parkinson's disease (PD) (Conte et al., 2021), and glioma cell necroptosis (Wang et al., 2022). These results suggest that CypA plays an important role in AIF‐mediated cell death, and their nuclear translocation is interdependent.…”