Neuroprotection by a Secreted Component of the Cellular Stress Response

项目摘要 我们认为ER膜结合转录因子CREB 3L 2的分泌型管腔结构域， TAILS是神经元中适应性细胞应激反应的传递信号。此前，我们发现 中枢神经系统神经元暴露于各种变性刺激，包括氧化应激，分泌TAILS。 将低纳摩尔浓度的TAILS应用于原代神经元改善了在氧化条件下的存活率。 应力TAILS通过增加SHH信号传导和增加线粒体适应性和氧化还原能力发挥作用， 紧张的神经元在我们的初步实验中，我们发现TAILS不仅能增强神经元的弹性， 对抗氧化损伤，也对抗由阿尔茨海默病的应用引发的应激 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脑中神经元的综合应激反应触发了TAILS的产生和分泌，TAILS起作用 作为旁分泌信号，增强SHH信号传导，从而增强对Aβ1-42诱导的神经元应激的恢复力。 该研究项目的成功完成将揭示一种新的非细胞自主分支， 适应性应激信号传导，其在神经元中响应神经变性应激而被激活，并赋予 增强了对接受细胞的弹性和线粒体功能。该项目的预期成果将 建立TAILS作为AD中保护性神经元SHH信号传导的应激调节调节剂， 哺乳动物神经系统中ISR细胞间通讯的证据， 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TAILS分泌的要求表明，它可能是有用的生物标志物， 大脑中的早期退行性疾病;和（2）TAILS（或由其衍生的肽）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.