Abstract W P99: OCT4B-190 Exerts Neuroprotection After Stroke by Regulating GSK-3β and HDAC-6

Backgrounds and Objectives: OCT4 is a key regulator in maintaining the pluripotency and self-renewal of embryonic stem cells (ESCs). Human OCT4 gene has three mRNA isoforms, termed OCT4A, OCT4B, and OCT4B1. OCT4A mRNA can translate into OCT4A protein. OCT4B mRNA has been recently found to generate three protein isoforms by alternative translation initiation, including the 265-amino-acid protein isoform OCT4B-265, the 190-amino-acid protein isoform OCT4B-190, and the 164-amino-acid protein isoform OCT4B-164. OCT4A is now widely recognized as a transcription factor responsible for the stemness of ESCs, while the biological functions of OCT4B protein isoforms are still not identified. A previous study showed that OCT4B-190 functioned in stress response. In this study, we further investigated biological roles of OCT4B-190 in stroke setting in vivo and in vitro . Methods and Results: Using primary neuron cultures, we demonstrated that OCT4B-190 overexpression enhanced neuronal viability 24hr after oxygen-glucose deprivation (OGD) treatment, with downregulated OGD-induced histone deacetylase 6 (HDAC6) and glycogen synthase kinase-3 (GSK-3). Furthermore, it was shown that HDAC6 and GSK3 were co-expressed in the cytosol of neurons, and OCT4 had an effect on interactions between HDAC6 and GSK3 after OGD that could be mimicked by GSK-3 inhibitors. Moreover, in male C57BL/6 mice subjected to transit middle cerebral artery occlusion (tMCAO), OCT4B-190 overexpression reduced post-stroke infarct volume and improved neurological functions at 3d after stroke. In addition, OCT4B-190 demonstrated similar impacts on HDAC6 and GSK3 alterations after MCAO treatment. Conclusions: These evidence suggest that OCT4B-190 exerts neuroprotection potentially by regulating GSK-3/HDAC6 pathway in ischemic stroke.