Abstract
Homer1a is the short form of a scaffold protein that plays a protective role in many forms of stress. However, the role of Homer1a in cerebral ischemia/reperfusion (I/R) injury and its potential mechanism is still unknown. In this study, we found that Homer1a was upregulated by oxygen and glucose deprivation (OGD) and that overexpression of Homer1a alleviated OGD-induced lactate dehydrogenase (LDH) release and cell death in cultured cortical neurons. After OGD treatment, the overexpression of Homer1a preserved mitochondrial function, as evidenced by less cytochrome c release, less reactive oxygen species (ROS) production, less ATP and mitochondrial membrane potential (MMP) loss, less caspase-9 activation, and inhibition of endoplasmic reticulum (ER) stress confirmed by the decreased expression of phosphate-PKR-like ER Kinase (p-PERK)/PERK and phosphate- inositol-requiring enzyme 1 (p-IRE1)/IRE1 and immunofluorescence (IF) staining. In addition, mitochondrial protection of Homer1a was blocked by the ER stress activator Tunicamycin (TM) with a re-escalated ROS level, increasing ATP and MMP loss. Furthermore, Homer1a overexpression-induced mitochondrial stress attenuation was significantly reversed by activating the PERK pathway with TM and p-IRE1 inhibitor 3,5-dibromosalicylaldehyde (DBSA), as evidenced by increased cytochrome c release, increased ATP loss and a higher ROS level. However, activating the IRE1 pathway with TM and p-PERK inhibitor GSK2656157 showed little change in cytochrome c release and exhibited a moderate upgrade of ATP loss and ROS production in neurons. In summary, these findings demonstrated that Homer1a protects against OGD-induced injury by preserving mitochondrial function through inhibiting the PERK pathway. Our finding may reveal a promising target of protecting neurons from cerebral I/R injury.
Highlights
Ischemic stroke (IS) is a sudden medical condition in which little or restricted blood flow to the brain results in cell death
To determine the effect of ischemic reperfusion (I/R) injury on Homer1a, the cultured cortical neurons were treated with oxygen and glucose deprivation (OGD) for 1 h, and the expression level of Homer1a protein at different reoxygenation time points was investigated using Western blot
We revealed that Homer1a protects against neuronal I/R injury by preserving mitochondrial function and regulating ERS in primary cortical neurons
Summary
Ischemic stroke (IS) is a sudden medical condition in which little or restricted blood flow to the brain results in cell death. The exact molecular pathways underlying the ischemic reperfusion (I/R) neuronal injury have not been fully illustrated. Homer proteins are best known as scaffold proteins located at the postsynaptic density and are crucial in regulating neuronal signals (Huang et al, 2008). Homer1a, a short form of Homer protein, contains a conserved EVH1 domain but lacks the CC domain, which enables Homer1a to function as a negative regulator of long forms of Homer protein (Foa and Gasperini, 2009). Our previous study showed that Homer1a protects neurons against N-Methyl-D-aspartate (NMDA)-induced injury (Wang et al, 2015), and we found that Homer1a protects retinal ganglion cells against retinal I/R injury (Fei et al, 2015). The exact role of Homer1a in cerebral I/R injury and the associated mechanism have not been elucidated
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