Neuroprotection by a Secreted Component of the Cellular Stress Response

项目总结 我们认为内质网膜结合转录因子CREB3L2的分泌腔结构域， Tail，是神经元中传递适应性细胞应激反应的信号。之前，我们发现 中枢神经系统神经元暴露在包括氧化应激在内的各种退行性刺激下，会分泌尾巴。 低纳摩尔浓度的尾巴应用于原代神经元可提高氧化条件下的存活率 压力。TAILS通过增加SHH信号，增加线粒体适合性和氧化还原能力而发挥作用 紧张的神经元。在我们的初步实验中，我们发现尾巴不仅增强了神经元的弹性 对抗氧化侮辱，也对抗阿尔茨海默病的应用所引发的压力 多肽寡聚体Aβ1-42。在这个提议中，我们正在测试我们的一般假设，即激活 AD大脑神经元的综合应激反应触发尾巴的产生和分泌，尾巴的作用 作为旁分泌信号，增强SHH信号，从而增强对Aβ1-42诱导的神经元应激的恢复能力。 这项研究项目的成功完成将揭示一个新的非细胞自治分支 神经元中激活的适应性应激信号，以响应神经退行性应激并赋予 增强了对接收细胞的韧性和线粒体功能。这个项目的预期结果将是 建立Tail作为AD保护性神经元SHH信号的应激调节调节器，它将提供 哺乳动物神经系统中ISR细胞间通讯的证据及其对 神经退行性疾病。此外，该项目将为两个主要的新方向奠定基础：(1) 细胞应激对尾巴分泌的要求表明，它可能是一种有用的生物标志物 大脑的早期退化状态；和(2)尾巴(或从尾巴衍生的多肽)是潜在的化合物 用于在AD和其他退行性疾病的背景下增强神经元的弹性。

PROJECT SUMMARY We propose that the secreted luminal domain of the ER membrane-bound transcription factor CREB3L2, TAILS, is a signal for the transmission of adaptive cell stress response in neurons. Previously, we discovered that CNS neurons exposed to variety of degenerative stimuli, including oxidative stress, secrete TAILS. Application of TAILS in a low nanomolar concentration to primary neurons improved survival under oxidative stress. TAILS acts by increasing SHH signaling and increasing the mitochondrial fitness and redox capacity in stressed neurons. In our preliminary experiments, we found that TAILS boosts neuronal resilience not only against oxidative insults but also against stress triggered by the application of the Alzheimer's disease peptide oligomeric Aβ1-42. In this proposal, we are testing our general hypothesis that activation of the integrated stress response in neurons in AD brain triggers the production and secretion of TAILS, which acts as a paracrine signal enhancing SHH signaling thereby boosting resilience to Aβ1-42-induced neuronal stress. The successful completion of this research project will uncover a novel non-cell autonomous branch of adaptive stress signaling that is activated in neurons in response neurodegenerative stress and confers enhanced resilience and mitochondrial function to receiving cells. The expected results from this project will establish TAILS as a stress-regulated modulator of protective neuronal SHH signaling in AD, and it will provide evidence for intercellular communication of the ISR in the mammalian nervous system with implications for neurodegenerative conditions. Moreover, this project will lay the groundwork for two major new directions: (1) the requirement of cell stress for the secretion of TAILS suggests that it might be useful as a biomarker for early degenerative conditions in the brain; and (2) TAILS (or peptides derived from it) are potential compounds for boosting neuronal resilience in the context of AD and other degenerative conditions.