Abstract TP301: Tmem30a - Mediated Mitigation of Phosphatidylserine Exposure May Be a Novel Therapeutic Target for Brain Protection in Ischemic Stroke

Abstract

Cellular pathways of self-preservation are highly conserved and may represent powerful ways to protect tissue against injury and disease. Here, we use a combination of cell, mouse, rat, nonhuman primate, and human models to demonstrate the feasibility of evoking endogenous self-preservation pathways to protect brain tissue in stroke. The transmembrane protein 30A ( Tmem30a ), the β-subunit of P4-ATPases, helps maintain the asymmetric distribution of phospholipids in plasma membrane, especially phosphatidylserine (PS) in the inner leaflet. Tmem30a transcripts were increased in the penumbra in two types of animal models of stroke. The increased Tmem30a transcripts were associated with less PS exposure and neuron death in vitro and improved neurological outcomes and extended therapeutic window in vivo. Mechanistically, Tmem30a upregulation led to decreased levels of apoptosis-related markers. Moreover, we found that recombinant Annexin V protein can decrease PS exposure, reduce infarct volumes, and improve neurological impairments in wild mice after ischemia/reperfusion, but not in Tmem30a knockout mice and those receiving siRNA- Tmem30a . Lastly, we also observed that high Annexin V levels were associated with better outcomes in stroke patients with salvageable penumbra, but not in those without penumbral tissues. Overall, our findings reveal a previously unappreciated role of maintaining asymmetric distribution of phospholipids in protecting the penumbra in the context of clinically relevant reperfusion. Tmem30a is essential for PS-blocking dependent neuroprotection and might represent a potential new strategy for evoking endogenous self-preservation pathways to protect brain tissue after stroke.