Interdependencies of autophagy, protein synthesis, aging, activity and synaptic viability.

自噬、蛋白质合成、衰老、活性和突触活力的相互依赖性。

• 批准号: 466163010
• 负责人: Professorin Dr. Daniela C. Dieterich
• 金额: --
• 依托单位: Institut für Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/466163010?language=en
• 关键词: Interdependencies; autophagy; protein; synthesis; aging

Synapses in the brain can persist for months and even years. Their proteinaceous components, however, become dysfunctional after much shorter periods, and thus must be continuously removed and degraded. Autophagy is one such removal pathway, mainly involved in clearance of protein complexes and aggregates. Significant evidence suggests that aging is associated with impaired protein clearance, and that manipulations that augment autophagy increase life-span and rejuvenate multiple physiological processes including several pertaining to synaptic and cognitive functions. As a rule, catabolic and anabolic processes are tightly coupled, and thus manipulations that enhance autophagy are likely to affect other aspects of protein metabolism, in particular protein synthesis. Our goal here is, thus, to gain a broader view of the effects exerted by such manipulations, using them to expose interdependencies among autophagy, protein synthesis, aging, activity, and synaptic viability. To that end we will examine how spermidine and its derivative hypusine impact (synaptic) protein synthesis and degradation in standard and aged neuronal cultures, in mice of different ages, and in mice raised in enriched environments. Long-term imaging will be used to examine how these manipulations affect autophagic flux, neuronal viability, synaptic persistence, tenacity and function, as well as resilience to stressors, in standard and aged neuronal cultures. Finally, we will use the obtained data to identify autophagy-associated druggable targets that might improve life-long neuronal and synaptic viability, and then, in collaboration with other FOR groups, test a subset of these. We expect that these findings will provide new insights on relationships among autophagy, protein synthesis, aging, activity and synaptic viability, and possibly uncover targets for useful pharmacological interventions.

大脑中的突触可以持续数月甚至数年。然而，它们的蛋白质成分在更短的时间内就会变得功能失调，因此必须不断去除和降解。自噬就是这样一种清除途径，主要涉及蛋白质复合物和聚集体的清除。重要证据表明，衰老与蛋白质清除受损有关，而增强自噬的操作可以延长寿命并恢复多种生理过程，包括与突触和认知功能有关的一些生理过程。一般来说，分解代谢和合成代谢过程是紧密耦合的，因此增强自噬的操作可能会影响蛋白质代谢的其他方面，特别是蛋白质合成。因此，我们的目标是更广泛地了解此类操作所产生的影响，利用它们来揭示自噬、蛋白质合成、衰老、活动和突触活力之间的相互依赖性。为此，我们将研究亚精胺及其衍生物hypusine如何影响标准和老化神经元培养物、不同年龄的小鼠以及在丰富环境中饲养的小鼠中的（突触）蛋白质合成和降解。长期成像将用于检查这些操作如何影响标准和老化神经元培养物中的自噬通量、神经元活力、突触持久性、韧性和功能以及对压力源的恢复能力。最后，我们将利用获得的数据来确定与自噬相关的可药物靶标，这些靶标可能会改善终生神经元和突触的活力，然后与其他 FOR 小组合作，测试其中的一个子集。我们期望这些发现将为自噬、蛋白质合成、衰老、活性和突触活力之间的关系提供新的见解，并可能揭示有用的药理学干预的目标。