title: Blocking Daxx trafficking attenuates neuronal cell death following ischemia/reperfusion in rat hippocampus CA1 region.
abstract: Previous studies have shown that the death-associated protein (Daxx) shuttles between nucleus and cytoplasm under ischemic stress, and the subcellular localization of Daxx plays an important role in ischemic neuron death. In this study, by blocking the Daxx trafficking, the rat hippocampus CA1 neurons were protected against cerebral ischemia/reperfusion, and the molecular mechanism underlying this neuroprotection was studied. We found that pretreatment of SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), or an anti-oxidant, N-acetylcysteine (NAC), could not only prevent Daxx from trafficking but also increase the number of the surviving CA1 pyramidal cells of hippocampus at 5days of reperfusion. Furthermore, knock-down of endogenous Daxx exerted similar neuroprotective effect during ischemia/reperfusion. We found the treatment of SP600125 or NAC could decrease the activation of Ask1 during ischemia/reperfusion and suppress the assembly of the Fas·Daxx·Ask1 signaling module, and in succession inhibit JNK activation and c-Jun phosphorylation. This study provides the Daxx trafficking as a new potential therapeutic target for ischemic brain injury.
authors.affiliation: Research Center for Biochemistry and Molecular Biology, Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, China.
authors.forename: Yu-Lan
authors.initials: YL
authors.lastname: Niu
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.forename: Guang-Yi
authors.initials: GY
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D016923:Cell Death; D017931:DNA Primers; D008297:Male; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; C528558:Daxx protein, rat; D018832:Molecular Chaperones; D009687:Nuclear Proteins