Rolle der Hypusinierung für die Translationssteuerung im alternden Gehirn
Zusammenfassung der Projektergebnisse
Cognitive decline during brain aging represents a major public health challenge, with ageinduced memory impairment (AMI) recognized as a leading risk factor for neurodegenerative disease. While mitochondrial dysfunction and synaptic degeneration have been implicated in this process, the mechanistic links between metabolic aging, synaptic resilience, and memory formation remained poorly understood at the time of proposal. Disentangling causative from compensatory changes in the aging brain posed a major challenge. Mounting evidence had pointed to mitochondria as key regulators of synaptic maintenance and neuronal plasticity, particularly due to their roles in ATP production and calcium homeostasis at synaptic sites. Age-associated impairments in mitochondrial respiration and redox balance, as well as a decline in synaptic structure and function, were thought to impair memory consolidation. At the same time, autophagy—and specifically mitophagy—had emerged as a critical resilience mechanism in aging, with dietary spermidine supplementation (Spd-S) shown to restore mitochondrial integrity and delay AMI in Drosophila. Preliminary data from our group had shown that Spd-S not only preserved mitochondrial function in aging flies, but also prevented the emergence of presynaptic remodeling (“PreScale”), a metaplastic change linked to impaired memory consolidation. A novel finding that motivated this proposal was the discovery that spermidine serves as a precursor for the post-translational hypusination of eIF5A, a process essential for translation elongation and mitochondrial protein synthesis. Initial results indicated that eIF5A hypusination declines with age and that its disruption impairs mitochondrial function, synaptic structure, and memory performance—suggesting that this modification could play a central role in preserving brain resilience. The goal of this project was to define the role of eIF5A hypusination in maintaining mitochondrial and synaptic function in the aging brain, and to explore its mechanistic contribution to memory consolidation and cognitive resilience. Specifically, we aimed to: • Determine whether dietary spermidine acts through eIF5A hypusination to preserve mitochondrial and synaptic function during aging. • Dissect the impact of hypusination on proteostasis, with particular attention to mitochondrial and synaptic protein classes. • Identify translational targets under the control of eIF5A^H in aging neurons. • Compare the mechanism of spermidine with other nutritional interventions such as protein restriction to identify overlapping and distinct pathways contributing to brain resilience.
Projektbezogene Publikationen (Auswahl)
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eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction. Cell Reports, 35(2), 108941.
Liang, YongTian; Piao, Chengji; Beuschel, Christine B.; Toppe, David; Kollipara, Laxmikanth; Bogdanow, Boris; Maglione, Marta; Lützkendorf, Janine; See, Jason Chun Kit; Huang, Sheng; Conrad, Tim O.F.; Kintscher, Ulrich; Madeo, Frank; Liu, Fan; Sickmann, Albert & Sigrist, Stephan J.
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Spermidine-induced hypusination preserves mitochondrial and cognitive function during aging. Autophagy, 17(8), 2037-2039.
Hofer, Sebastian J.; Liang, YongTian; Zimmermann, Andreas; Schroeder, Sabrina; Dengjel, Jörn; Kroemer, Guido; Eisenberg, Tobias; Sigrist, Stephan J. & Madeo, Frank
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The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity. EMBO Molecular Medicine, 14(5).
Ring, Julia; Tadic, Jelena; Ristic, Selena; Poglitsch, Michael; Bergmann, Martina; Radic, Nemanja; Mossmann, Dirk; Liang, YongTian; Maglione, Marta; Jerkovic, Andrea; Hajiraissi, Roozbeh; Hanke, Marcel; Küttner, Victoria; Wolinski, Heimo; Zimmermann, Andreas; Domuz Trifunović, Lana; Mikolasch, Leonie; Moretti, Daiana N.; Broeskamp, Filomena ... & Madeo, Frank
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Spermidine is essential for fasting-mediated autophagy and longevity. Nature Cell Biology, 26(9), 1571-1584.
Hofer, Sebastian J.; Daskalaki, Ioanna; Bergmann, Martina; Friščić, Jasna; Zimmermann, Andreas; Mueller, Melanie I.; Abdellatif, Mahmoud; Nicastro, Raffaele; Masser, Sarah; Durand, Sylvère; Nartey, Alexander; Waltenstorfer, Mara; Enzenhofer, Sarah; Faimann, Isabella; Gschiel, Verena; Bajaj, Thomas; Niemeyer, Christine; Gkikas, Ilias; Pein, Lukas ... & Madeo, Frank
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Coupling of mitochondrial state with active zone plasticity in early brain aging. Redox Biology, 79, 103454.
Fei, Lu; Liang, Yongtian; Kintscher, Ulrich & Sigrist, Stephan J.
