MLKL inhibition attenuates hypoxia-ischemia induced neuronal damage in developing brain
Authors: Xuemei Lin
Jun Tang
Fengyan Zhao
Ying Tang
Shiping Li
Yi Qu
Junjie Meng
Jing Shi
Xiaodong Peng
Dezhi Mu
Journal: Experimental Neurology (2016)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Brain damage; Hypoxia-ischemia; MLKL; Neonate; Neuron.
Affiliations: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China. Electronic address: ., Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China., Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China., Department of Experimental Medicine, West China First University Hospital, Sichuan University, Chengdu 610041, China., Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: .

Abstract:  Mixed lineage kinase domain-like protein (MLKL) is a critical molecule mediating cell necroptosis. However, its role in brain injury remains obscure. We first investigated the functions and mechanisms of MLKL in mediating neuronal damage in developing brain after hypoxia-ischemia. Neuronal necroptosis was induced by oxygen-glucose deprivation (OGD) plus caspase inhibitor zVAD treatment (OGD/zVAD). We found that two important necroptosis related proteins, receptor-interacting protein 1 and 3 (RIP1, RIP3) were upregulated. Furthermore, the interaction of RIP1-RIP3 with MLKL increased. Inhibition of MLKL through siRNA diminished RIP1-RIP3-MLKL interaction and attenuated neuronal death induced by OGD/zVAD. The translocation of oligomerized MLKL to the neuronal membrane leading to the injury of cellular membrane is the possible new mechanism of neuronal necroptosis. Animal experiment with neonatal rats further proved that MLKL inhibition attenuated brain damage induced by hypoxia-ischemia. These findings suggest that MLKL is a target to attenuate brain damage in developing brain. 

Retracted: No

PubPeer comments:
 Figure 1C. The OGD and OGD zVAD panels appear to share more features than expected. Could the authors please show us the raw data? ![file] , 
 Dear Dr. Bik, Thank you very much for pointing out this mistake of Figurer 1 C of the paper. I am the co-corresponding author of the paper. I have contacted the first author and the first corresponding author to carefully check the figure and will response to you as soon as possible. Sincerely, Dezhi Mu , 
 Dear Dr. Bik, Iu2019m the first author and co-corresponding author, Yi Qu, of the paper. Thank you very much for helping us to find out the mistakes and errors. We are now checking the original data, especially the figures from the collaborating units. We are very sorry for these mistakes. , 
 #3  We are now checking the original data, especially the figures from the collaborating units. As an interested by-stander, I want to thank Yi Qu (in addition to the corresponding author) for responding so promptly. I have to ask, though, who are these  collaborating units ? Do you mean your co-authors, or someone not listed in the author list or the Author Contribution paragraph? ,