Brain Research Centre, Vancouver, British Columbia, Canada.
J Neurosci. 2011 Aug 17;31(33):11980-91. doi: 10.1523/JNEUROSCI.2510-11.2011.
Although the palmitoyl acyltransferase (PAT) zinc-finger DHHC containing 17 (zD17) has been implicated in genetic neurological disorders by regulating protein palmitoylation, the role of zD17 in acute brain injury remains unknown. Here, we report that zD17 contributes to acute ischemic brain injury via a mechanism independent of its PAT activity. We have found that zD17 directly interacts with c-Jun N terminus kinase (JNK) to form a signaling module for JNK activation. Pathological stressors induce the zD17-JNK interaction, which promotes downstream neuronal cell death signals. We have developed novel peptides targeting the JNK-interacting motif on zD17 to selectively block the enhancement of the zD17-JNK interaction and the activation of JNK isoforms 2 and 3. Application of these peptides successfully blocks JNK activation and neuronal cell death pathways, protects cultured neurons from excitotoxicity, and dramatically reduces brain damage and behavioral deficits in a rat model of focal ischemic stroke. Our findings indicate zD17 as a key player in ischemic stroke and suggest the potential therapeutic value of targeting the zD17-JNK interaction for acute brain injury.
尽管棕榈酰基转移酶（PAT）锌指 DHHC 结构域 17（zD17）通过调节蛋白质棕榈酰化作用而与遗传神经疾病有关，但 zD17 在急性脑损伤中的作用仍不清楚。在这里，我们报告 zD17 通过一种独立于其 PAT 活性的机制参与急性缺血性脑损伤。我们发现 zD17 直接与 c-Jun N 末端激酶（JNK）相互作用，形成 JNK 激活的信号模块。病理应激诱导 zD17-JNK 相互作用，促进下游神经元细胞死亡信号。我们开发了针对 zD17 上 JNK 相互作用基序的新型肽，以选择性阻断 zD17-JNK 相互作用的增强和 JNK 同工型 2 和 3 的激活。这些肽的应用成功阻断了 JNK 激活和神经元细胞死亡途径，保护培养神经元免受兴奋性毒性，并且在局灶性缺血性中风大鼠模型中显著减少脑损伤和行为缺陷。我们的研究结果表明 zD17 是缺血性中风的关键参与者，并表明针对 zD17-JNK 相互作用的治疗急性脑损伤的潜在价值。
