The role of hypusination-dependent translation for brain aging

兴奋依赖翻译对大脑衰老的作用

• 批准号: 445178831
• 负责人: Professor Dr. Stephan J. Sigrist
• 金额: --
• 依托单位: Institut für Biologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/445178831?language=en
• 关键词: role; hypusination; dependent; translation; brain

Mitochondrial function and synaptic performance decline during brain aging, processes suspected of key roles in the age-induced functional decline of the brain. Dietary and consequently metabolic reprogramming might be able to restrict such age-induced deficits. Our recent unpublished work shows that spermidine supplementation (Spd-S) protects mitochondrial respiration aging Drosophila brains. We have just found that this spermidine (Spd) effect depends on a rare posttranslational modification called hypusination, i.e. the catalytic conjugation of the aminobutyl moiety of Spd to eukaryotic translation initiation factor 5A, a process found to decay in aging mouse brains. Our genetic attenuation of hypusination not only reduced mitochondrial respiratory capacity and occluded the anti-aging effects of Spd-S on mitochondrial status in Drosophila brains but also on memory capacity and locomotion function.We here suggest exploring the functional role of hypusination-dependent translation regulation for neuronal, synaptic and mitochondrial integrity in the aging Drosophila brain. We will execute a proteomic and translation-mechanistic analysis to identify transcripts with hypusination-sensitive translation and, subsequently, through a CRISPR/Cas9 approach, manipulate the hypusination-dependence of relevant substrate transcripts. This will finally allow us to investigate causal relations between autophagy and hypusination for protecting critical brain functions (learning and memory, locomotion) in Drosophila, concentrating on the interplay between mitochondria and synapses. The principal goal of this application is to deepen the understanding i) whether and to which degree hypusination decline drives aspects of brain aging and ii) whether a restoration of hypusination via Spd-S is functionally involved in the protective effects of Spd-S. Notably, hypusination is a highly conserved process, and the newest genetic evidence shows that a mild genetic attenuation of the hypusination level (< 40 %) already provokes a severe, largely nervous system-specific phenotype in humans. However, the role of hypusination-controlled translation regulation in the brain is still a terra incognita. Thus, this project will instruct our analysis in rodent models and our results will provide a principal insight into the pathological relevance of hypusination and, thus, in the long run, become relevant from a medical perspective as well.

线粒体功能和突触功能在大脑衰老过程中下降，这些过程被怀疑是年龄诱导的大脑功能下降的关键作用。饮食和由此产生的代谢重编程可能能够限制这种年龄引起的缺陷。我们最近未发表的研究表明，补充亚精胺（Spd-S）可以保护线粒体呼吸老化的果蝇大脑。我们刚刚发现，这种亚精胺（Spd）的作用依赖于一种罕见的翻译后修饰，称为hypusination，即Spd的氨基丁基部分与真核翻译起始因子5A的催化偶联，这一过程在衰老的小鼠大脑中被发现会衰减。我们的基因抑制不仅降低了果蝇线粒体的呼吸能力，阻断了Spd-S对线粒体状态的抗衰老作用，而且还影响了果蝇的记忆能力和运动功能。我们建议在衰老的果蝇大脑中探索假说依赖的翻译调节对神经元、突触和线粒体完整性的功能作用。我们将执行蛋白质组学和翻译机制分析，以鉴定具有hyphypination敏感翻译的转录本，随后，通过CRISPR/Cas9方法，操纵相关底物转录本的hyphypination依赖性。这将最终使我们能够研究自噬和假说之间的因果关系，以保护果蝇的关键大脑功能（学习和记忆，运动），集中在线粒体和突触之间的相互作用。本应用程序的主要目标是加深理解i)假设衰退是否以及在多大程度上驱动脑衰老的各个方面，ii)通过Spd-S恢复假设是否在功能上参与Spd-S的保护作用。值得注意的是，hypusination是一个高度保守的过程，最新的遗传证据表明，hypusination水平的轻微遗传衰减（< 40%）已经在人类中引起严重的，主要是神经系统特异性表型。然而，假说控制的翻译调控在大脑中的作用仍是一个未知领域。因此，这个项目将指导我们对啮齿动物模型的分析，我们的结果将为假说的病理相关性提供主要见解，因此，从长远来看，从医学角度来看也是相关的。