title: TRAF1 is a critical regulator of cerebral ischaemia-reperfusion injury and neuronal death.
abstract: Stroke is a leading global cause of mortality and disability. Less than 5% of patients are able to receive tissue plasminogen activator thrombolysis within the necessary timeframe. Focusing on the process of neuronal apoptosis in the penumbra, which lasts from hours to days after ischaemia, appears to be promising. Here we report that tumour necrosis factor receptor-associated factor 1 (TRAF1) expression is markedly induced in wild-type mice 6 h after stroke onset. Using genetic approaches, we demonstrate that increased neuronal TRAF1 leads to elevated neuronal death and enlarged ischaemic lesions, whereas TRAF1 deficiency is neuroprotective. In addition, TRAF1-mediated neuroapoptosis correlates with the activation of the JNK pro-death pathway and inhibition of the Akt cell survival pathway. Finally, TRAF1 is found to exert pro-apoptotic effects via direct interaction with ASK1. Thus, ASK1 positively and negatively regulates the JNK and Akt signalling pathways, respectively. Targeting the TRAF1/ASK1 pathway may provide feasible therapies for stroke long after onset.
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China [2] Cardiovascular Research Institute of Wuhan University, Wuhan 430060, China [3].
authors.forename: Yan-Yun
authors.initials: YY
authors.lastname: Lu
authors.forename: Zuo-Zhi
authors.initials: ZZ
authors.lastname: Li
authors.forename: Ding-Sheng
authors.initials: DS
authors.lastname: Jiang
authors.forename: Lang
authors.initials: L
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Liu
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D047990:TNF Receptor-Associated Factor 1; D051057:Proto-Oncogene Proteins c-akt