The degradation of mixed lineage kinase domain-like protein promotes neuroprotection after ischemic brain injury.

Yanlong Zhou,Yan Tang,Zhong Zhao,Yanbo Chen,Zhigang Miao,Chen Xu,Hui Tu,Beiqun Zhou

doi:10.18632/oncotarget.19416

Abstract

Mixed lineage kinase domain-like (MLKL) protein was recently found to play a critical role in necrotic cell death. To explore its role in neurological diseases, we measured MLKL protein expression after ischemia injury in a mouse model. We found that MLKL expression significantly increased 12 h after ischemia/reperfusion (I/R) injury with peak levels at 48 h. Inhibition of MLKL by intraperitoneal administration of NSA significantly reduced infarct volume and improved neurological deficits after 75 min of ischemia and 24 h of reperfusion. Further, we found NSA reduced MLKL levels via the ubiquitination proteasome pathway, but not by inhibiting RNA transcription. Interestingly, NSA administration increased cleaved PARP-1 levels, indicating the protective effects of MLKL inhibition is not related to apoptosis. These findings suggest MLKL is a new therapeutic target for neurological pathologies like stroke. Therefore, promoting degradation of MLKL may be a novel avenue to reduce necrotic cell death after ischemic brain injury.

Highlights

Mixed-lineage kinase domain-like (MLKL) protein is a pseudokinase and downstream target of Receptor Interaction Protein kinase 3 (RIP3)
Previous studies have indicated that Mixed lineage kinase domain-like (MLKL) plays a critical role in the process of RIP1/RIP3 complexinduced necrosis in vitro [7]
The results demonstrated that ischemic brain injury increased MLKL expression at the early stage of cerebral ischemia

Summary

Introduction

Mixed-lineage kinase domain-like (MLKL) protein is a pseudokinase and downstream target of Receptor Interaction Protein kinase 3 (RIP3). In order to study necrotic signaling pathways, drug screens have been used to identify necrosis inhibitors like necrostatin-1 and Necrosulfonamide (NSA) [2, 7]. Necrostatin-1 is a RIP1 inhibitor that blocks TNF-induced necrosis and reduces infarct size after cerebral ischemia injury [1, 2]. A recent study indicated that low MLKL expression is associated with poor prognosis in ovarian cancer patients [9]. This hints a role for MLKL in necrotic cell death in tumors and other diseases. Our results suggested that MLKL is a potential therapeutic target for ischemic stroke treatment

Methods

Results

Conclusion