Davis Angela R, Lotocki George, Marcillo Alex E, Dietrich W Dalton, Keane Robert W
Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
J Neurotrauma. 2007 May;24(5):823-34. doi: 10.1089/neu.2006.0227.
The Fas/CD95 receptor-ligand system plays an essential role in apoptosis that contributes to secondary damage after spinal cord injury (SCI), but the mechanism regulating the efficiency of FasL/Fas signaling in the central nervous system (CNS) is unknown. Here, FasL/Fas signaling complexes in membrane rafts were investigated in the spinal cord of adult female Fischer rats subjected to moderate cervical SCI and sham operation controls. In sham-operated animals, a portion of FasL, but not Fas was present in membrane rafts. SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). Moreover, SCI induced expression of Fas in clusters around the nucleus in both neurons and astrocytes. The formation of the DISC signaling platform leads to rapid activation of initiator caspase-8 and effector caspase-3, and the modification of signaling intermediates such as FADD and cFLIP(L) . Thus, FasL/Fas-mediated signaling after SCI is similar to Fas expressing Type I cell apoptosis.
Fas/CD95受体-配体系统在凋亡过程中发挥着重要作用，而凋亡会导致脊髓损伤（SCI）后的继发性损伤，但调节中枢神经系统（CNS）中FasL/Fas信号传导效率的机制尚不清楚。在此，对成年雌性Fischer大鼠进行中度颈椎SCI并设置假手术对照组，研究其脊髓中膜筏内的FasL/Fas信号复合物。在假手术动物中，膜筏中存在一部分FasL，但不存在Fas。SCI导致FasL和Fas易位至膜筏微结构域，在该结构域中Fas与衔接蛋白Fas相关死亡结构域（FADD）、半胱天冬酶-8、细胞型FLIP长链（cFLIPL）和半胱天冬酶-3结合，形成死亡诱导信号复合物（DISC）。此外，SCI诱导神经元和星形胶质细胞核周围簇状Fas表达。DISC信号平台的形成导致起始半胱天冬酶-8和效应半胱天冬酶-3的快速激活，以及FADD和cFLIP(L)等信号中间体的修饰。因此，SCI后FasL/Fas介导的信号传导类似于表达Fas的I型细胞凋亡。
