Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
Neurobiol Dis. 2012 May;46(2):393-401. doi: 10.1016/j.nbd.2012.02.003. Epub 2012 Feb 14.
Glaucoma is a neurodegenerative disease characterized by the apoptotic death of retinal ganglion cells (RGCs). The primary insult to RGCs in glaucoma is thought to occur to their axons as they exit the eye in the optic nerve head. However, pathological signaling pathways that exert central roles in triggering RGC death following axonal injury remain unidentified. It is likely that the first changes to occur following axonal injury are signal relay events that transduce the injury signal from the axon to the cell body. Here we focus on the c-Jun N-terminal kinase (JNK1-3) family, a signaling pathway implicated in axonal injury signaling and neurodegenerative apoptosis, and likely to function as a central node in axonal injury-induced RGC death. We show that JNK signaling is activated immediately after axonal injury in RGC axons at the site of injury. Following its early activation, sustained JNK signaling is observed in axonally-injured RGCs in the form of JUN phosphorylation and upregulation. Using mice lacking specific Jnk isoforms, we show that Jnk2 and Jnk3 are the isoforms activated in injured axons. Combined deficiency of Jnk2 and Jnk3 provides robust long-term protection against axonal injury-induced RGC death and prevents downregulation of the RGC marker, BRN3B, and phosphorylation of JUN. Finally, using Jun deficient mice, we show that JUN-dependent pathways are important for axonal injury-induced RGC death. Together these data demonstrate that JNK signaling is the major early pathway triggering RGC death after axonal injury and may directly link axon injury to transcriptional activity that controls RGC death.
青光眼是一种神经退行性疾病，其特征是视网膜神经节细胞（RGC）的凋亡死亡。人们认为，青光眼对 RGC 的主要损伤发生在视神经头部的轴突离开眼睛时。然而，在轴突损伤后触发 RGC 死亡的主要病理信号通路仍未确定。在轴突损伤后，很可能首先发生的是信号转导事件，这些事件将损伤信号从轴突传递到细胞体。在这里，我们重点关注 c-Jun N 端激酶（JNK1-3）家族，该信号通路与轴突损伤信号和神经退行性细胞凋亡有关，很可能作为轴突损伤诱导的 RGC 死亡中的中央节点发挥作用。我们表明，JNK 信号在 RGC 轴突中损伤部位的轴突损伤后立即被激活。在其早期激活之后，在轴突损伤的 RGC 中观察到持续的 JNK 信号，表现为 JUN 磷酸化和上调。使用缺乏特定 Jnk 同工型的小鼠，我们表明 Jnk2 和 Jnk3 是激活损伤轴突的同工型。Jnk2 和 Jnk3 的联合缺失为轴突损伤诱导的 RGC 死亡提供了强大的长期保护作用，并防止了 RGC 标志物 BRN3B 的下调和 JUN 的磷酸化。最后，使用 Jun 缺陷型小鼠，我们表明 JUN 依赖性途径对轴突损伤诱导的 RGC 死亡很重要。这些数据共同表明，JNK 信号是轴突损伤后触发 RGC 死亡的主要早期途径，并且可能直接将轴突损伤与控制 RGC 死亡的转录活性联系起来。
