Role of NMDA receptor-dependent activation of SRCBP1 in excitotoxic and ischemic neuronal injuries (Nat Med, 2009, 15:1399-1406)

報告日期: 2010/05/21
報告時間: 15:10/16:00
報告學生: 劉威廷(英文報告)
講評老師: 莊季瑛

Role of NMDA receptor-dependent activation of SREBP1 in excitotoxic and ischemic nueuronal injuries


Changiz Taghibiglou, Henry G S Martin, Ted Weita Lai, Taesup Cho, Shiv Prasad, Luba Kojic, Jie Lu, Yitao Liu, Edmund Lo, Shu Zhang, Julia Z Z Wu, Yu Ping Li, Yan Hua Wen, Joon-Hyuk Imm, Max S Cynader & Yu Tian Wang


Nature Medicine 15, 1399-1406, 2009  


Speaker: Wei-Ting Liu (劉威廷)    

Commentator: Jih-Ing Chuang, Ph.D. (莊季瑛 老師)

Time: 15:10-16:00, May 21, 2010

Place: room 602



    Neuronal damage after an acute brain insult, such as stroke and brain trauma, remains a major cause of morbidity and mortality worldwide and affects millions of lives every year. Many evidences suggest that neuronal excitotoxicity caused by overactivation of NMDA receptors (NMDARs) is a primary neuropathological process contributing to neuronal injury after stroke. However, several clinical trials have failed to find the expected efficacy of NMDAR antagonists in reducing brain injury due to the interference with crucial physiological NMDAR function. Thus, making new therapeutic targets are a matter of great importance. Several recent studies have suggested that activation of NMDARs has been linked to the modulation of a number of transcription factors, with either pro-neuronal survival or pro-death activity. Therefore, alternation of transcription factor activity may crucially contribute to excitotoxic neuronal injuries. Here, the authors used protein-DNA arrays to find an NMDAR -dependent activation of SREBP-1, a transcription factor well known for cholesterol and phospholipid biosynthesis. Emerging evidences suggested that activation of NMDARs could lead to pro-survival or pro-death signaling pathways depending on the subunit composition or subcellular location of the receptors. The authors found that the NMDA-induced SREBP-1 activation was through the NR2B-containing NMDAR, not NR2A. NMDAR activation promoted the ubiquitin-dependent degradation of Insig-1, insulin-induced gene-1, thereby enhancing the activation of SREBP-1. They also found that Insig-1 degradation and SREBP-1 activity increased during oxygen and glucose deprivation in neuronal cells, conditions that mimic ischemic stroke. These effects were inhibited with an Insig-1-derived interference peptide (Indip) that the authors have developed. Moreover, they found that Indip-mediated attenuation of SREBP-1 activation reduced brain damage in an in vivo model of stroke. Thus, these findings suggested that agents that reduce SREBP-1 activation such as Indip may present a new class of neuroprotective therapeutics against stroke.



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