Department of Functional Biology, CIBUS, Faculty of Biology, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Shriners Hospitals Pediatric Research Center (Center for Neural Repair and Rehabilitation), Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA 19140, USA.
Biomed Res Int. 2017;2017:5953674. doi: 10.1155/2017/5953674. Epub 2017 Nov 19.
Spinal cord injury (SCI) is a devastating condition that leads to permanent disability because injured axons do not regenerate across the trauma zone to reconnect to their targets. A prerequisite for axonal regeneration will be the prevention of retrograde degeneration that could lead to neuronal death. However, the specific molecular mechanisms of axotomy-induced degeneration of spinal-projecting neurons have not been elucidated yet. In lampreys, SCI induces the apoptotic death of identifiable descending neurons that are "bad regenerators/poor survivors" after SCI. Here, we investigated the apoptotic process activated in identifiable descending neurons of lampreys after SCI. For this, we studied caspase activation by using fluorochrome-labeled inhibitors of caspases, the degeneration of spinal-projecting neurons using Fluro-Jade C staining, and the involvement of the intrinsic apoptotic pathway by means of cytochrome c and V double immunofluorescence. Our results provide evidence that, after SCI, bad-regenerating spinal cord-projecting neurons slowly degenerate and that the extrinsic pathway of apoptosis is involved in this process. Experiments using the microtubule stabilizer Taxol showed that caspase-8 signaling is retrogradely transported by microtubules from the site of axotomy to the neuronal soma. Preventing the activation of this process could be an important therapeutic approach after SCI in mammals.
脊髓损伤 (SCI) 是一种破坏性疾病，会导致永久性残疾，因为受伤的轴突不会在创伤区域再生以重新连接到目标。轴突再生的一个前提条件是防止逆行退化，否则可能导致神经元死亡。然而，轴突切断诱导的投射神经元退行性变的具体分子机制尚未阐明。在七鳃鳗中，SCI 诱导可识别的下行神经元发生凋亡性死亡，这些神经元在 SCI 后是“不良再生者/不良存活者”。在这里，我们研究了 SCI 后七鳃鳗可识别下行神经元中激活的凋亡过程。为此，我们使用荧光标记的 caspase 抑制剂研究了 caspase 的激活，使用 Fluro-Jade C 染色研究了投射神经元的退化，并用细胞色素 c 和 V 双免疫荧光研究了内在凋亡途径的参与。我们的研究结果表明，在 SCI 后，不良再生的脊髓投射神经元会缓慢退化，并且凋亡的外在途径参与了这一过程。使用微管稳定剂紫杉醇的实验表明，caspase-8 信号通过微管从轴突切断部位逆行运输到神经元体。防止这个过程的激活可能是哺乳动物 SCI 后重要的治疗方法。
