机构：[1]Institute of Neuroscience, Soochow University, Suzhou City, Jiangsu Province, China[2]Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, China[3]Department of Neurology, The Second Affiliated Hospital of Jiaxing University, Jiaxing City, Zhejiang Province, China[4]Department of Anesthesia, The Second Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, China[5]Department of Neurology, The Affiliated Suzhou Hospital, Nanjing Medical University, Suzhou City, Jiangsu Province, China
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.
基金：
This work was supported by the grant from the National Natural Science Foundation of China (81601154), the grants from Jiangsu Province Health and Family Planning Commission (H201651) and Suzhou Science and Technology Bureau (Applied Basic Research Programs, SYS201650), and the Priority Academic Program Development of Jiangsu Higher Education Institutions of China.
第一作者机构：[1]Institute of Neuroscience, Soochow University, Suzhou City, Jiangsu Province, China[2]Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
共同第一作者：
通讯作者：
通讯机构：[1]Institute of Neuroscience, Soochow University, Suzhou City, Jiangsu Province, China[5]Department of Neurology, The Affiliated Suzhou Hospital, Nanjing Medical University, Suzhou City, Jiangsu Province, China
推荐引用方式(GB/T 7714)：
Yanlong Zhou,Beiqun Zhou,Hui Tu,et al.The degradation of mixed lineage kinase domain-like protein promotes neuroprotection after ischemic brain injury.[J].Oncotarget.2017,8(40):68393-68401.doi:10.18632/oncotarget.19416.
APA：
Yanlong Zhou,Beiqun Zhou,Hui Tu,Yan Tang,Chen Xu...&Zhigang Miao.(2017).The degradation of mixed lineage kinase domain-like protein promotes neuroprotection after ischemic brain injury..Oncotarget,8,(40)
MLA：
Yanlong Zhou,et al."The degradation of mixed lineage kinase domain-like protein promotes neuroprotection after ischemic brain injury.".Oncotarget 8..40(2017):68393-68401
医学