Mechanisms of neuroprotection against ischemic insult by stress‐inducible phosphoprotein‐1/prion protein complex

• Published in: Journal of neurochemistry 2018-04, Vol.145 (1), p.68-79
• Main Authors: Beraldo, Flavio H., Ostapchenko, Valeriy G., Xu, Jason Z., Di Guglielmo, Gianni M., Fan, Jue, Nicholls, Peter J., Caron, Marc G., Prado, Vania F., Prado, Marco A. M.
• Format: Article
• Language: English
• Subjects: Acetylcholine receptors (nicotinic); Activation; Activin; Activin Receptors, Type I - metabolism; ALK2; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Animals; Apoptosis; Apoptosis - physiology; Bone marrow; Bone morphogenetic protein 4; Brain; Brain Ischemia - metabolism; Cascades; Cell death; Cells, Cultured; Deprivation; Female; Heat-Shock Proteins - metabolism; Ischemia; Male; Mice; Mice, Inbred C57BL; Neurons; Neuroprotection; Neuroprotection - physiology; Pharmacology; Prion protein; Prion Proteins - metabolism; Protein Binding; Proteins; Receptors; Reperfusion; Rodents; Signal transduction; Signal Transduction - physiology; Signaling; Stem cell transplantation; Stem cells; STIP1; Stress‐inducible phosphoprotein 1; Stroke; α7nAChR
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14281

Stress‐inducible phosphoprotein 1 (STI1) acts as a neuroprotective factor in the ischemic brain and its levels are increased following ischemia. Previous work has suggested that some of these STI1 actions in a stroke model depend on the recruitment of bone marrow‐derived stem cells to improve outcomes after ischemic insult. However, STI1 can directly increase neuroprotective signaling in neurons by engaging with the cellular prion protein (PrPC) and activating α7 nicotinic acetylcholine receptors (α7nAChR). Given that α7nAChR activation has also been involved in neuroprotection in stroke, it is possible that STI1 can have direct actions on neurons to prevent deleterious consequences of ischemic insults. Here, we tested this hypothesis by exposing primary neuronal cultures to 1‐h oxygen‐glucose deprivation (OGD) and reperfusion and assessing signaling pathways activated by STI1/PrPC. Our results demonstrated that STI1 treatment significantly decreased apoptosis and cell death in mouse neurons submitted to OGD in a manner that was dependent on PrPC and α7nAChR, but also on the activin A receptor 1 (ALK2), which has emerged as a signaling partner of STI1. Interestingly, pharmacological inhibition of the ALK2 receptor prevented neuroprotection by STI1, while activation of ALK2 receptors by bone morphogenetic protein 4 (BMP4) either before or after OGD was effective in decreasing neuronal death induced by ischemia. We conclude that PrPC/STI1 engagement and its subsequent downstream signaling cascades involving α7nAChR as well as the ALK2 receptor may be activated in neurons by increased levels of STI1. This signaling pathway protects neurons from ischemic insults. Stress‐inducible phosphoprotein 1 (STI1) is a secreted co‐chaperone that exhibits neuroprotective properties in stroke. However, the mechanisms involved in neuronal protection by STI1 remain unknown. Here, we found that extracellular STI1 decreased apoptosis and cellular death in mouse neurons submitted to ischemic insult by modulating signaling by the prion protein, α7nAChR and activin A receptor 1 (ALK2). Our findings suggest that this pathway may protect neurons from ischemic insults during stroke.