The role of hypusination-dependent translation for brain aging

• Applicant: Professor Dr. Stephan J. Sigrist
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445178831

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 Our recent unpublished work shows that spermidine supplementation (Spd-S) protects mitochondrial respiration aging Drosophila brains.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.

• DFG Programme: Research Grants