Sertad1 Induces Neurological Injury after Ischemic Stroke via the CDK4/p-Rb Pathway

by Selleckchem | Jan 06 2024

SERTA domain-containing protein 1 (Sertad1) is upregulated in the models of DNA damage and Alzheimer's disease, contributing to neuronal death. However, the role and mechanism of Sertad1 in ischemic/hypoxic neurological injury remain unclear. In the present study, our results showed that the expression of Sertad1 was upregulated in a mouse middle cerebral artery occlusion and reperfusion model and in HT22 cells after oxygen-glucose deprivation/reoxygenation (OGD/R). Sertad1 knockdown significantly ameliorated ischemia-induced brain infarct volume, neurological deficits and neuronal apoptosis. In addition, it significantly ameliorated the OGD/R-induced inhibition of cell viability and apoptotic cell death in HT22 cells. Sertad1 knockdown significantly inhibited the ischemic/hypoxic-induced expression of p-Rb, B-Myb, and Bim in vivo and in vitro. However, Sertad1 overexpression significantly exacerbated the OGD/R-induced inhibition of cell viability and apoptotic cell death and p-Rb, B-Myb, and Bim expression in HT22 cells. In further studies, we demonstrated that Sertad1 directly binds to CDK4 and the CDK4 inhibitor ON123300 restores the effects of Sertad1 overexpression on OGD/R-induced apoptotic cell death and p-Rb, B-Myb, and Bim expression in HT22 cells. These results suggested that Sertad1 contributed to ischemic/hypoxic neurological injury by activating the CDK4/p-Rb pathway.

Comments:

It seems like the study you're referring to indicates that the protein Sertad1 plays a role in ischemic/hypoxic neurological injury by being upregulated during such conditions. Here's a breakdown of the findings:

1. **Upregulation in Ischemic/Hypoxic Conditions:** Sertad1 expression was found to increase in both a mouse model of middle cerebral artery occlusion and reperfusion, as well as in HT22 cells after oxygen-glucose deprivation/reoxygenation (OGD/R).

2. **Role in Neuronal Damage:** Knocking down Sertad1 showed promising results in reducing brain infarct volume, neurological deficits, and neuronal apoptosis in response to ischemia. It also helped in improving cell viability and inhibiting apoptotic cell death in HT22 cells under hypoxic conditions.

3. **Molecular Mechanisms:** The study identified that Sertad1 might exert its effects through the CDK4/p-Rb pathway. Sertad1 knockdown decreased the expression of p-Rb, B-Myb, and Bim, which are associated with cell cycle regulation and apoptosis. Conversely, overexpressing Sertad1 exacerbated the effects observed during OGD/R.

4. **Interaction with CDK4:** Sertad1 was found to directly bind to CDK4, a key regulator in cell cycle progression. The use of the CDK4 inhibitor ON123300 reversed the effects of Sertad1 overexpression, indicating that CDK4 might be a crucial player in Sertad1-mediated ischemic/hypoxic injury.

This study suggests that Sertad1's involvement in ischemic/hypoxic injury is linked to its influence on the CDK4/p-Rb pathway, contributing to cell cycle dysregulation and apoptotic cell death. Targeting this pathway, perhaps through CDK4 inhibition, might offer potential therapeutic avenues for managing neurological damage caused by ischemia or hypoxia.