Pre-Synapse to Nucleus Communication in Memory Function

• Applicant: Professor Dr. Michael R. Kreutz
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 424092638

• Final Report Year: 2024

Final Report Abstract

In this project we were dealing with the question whether macromolecular protein transport is involved in presynapse-to-nucleus communication. More specifically, we proposed that long-distance protein transport from presynapse-to-nucleus is important for cognitive faculties associated with dentate gyrus function. Importin β1-dependent axon to soma communication has been described in injury responses and axon growth of peripheral neurons, and the question how such pathways might impact on behavioral circuits is intriguing and largely unexplored. A second protein of interest was the synapto-nuclear messenger protein Jacob. Jacob is known to couple NMDA-receptor derived calcium signals to the activation of the transcription factor CREB. Following importinmediated retrograde protein transport from synapse-to-nucleus Jacob docks a signalosome to CREB that regulates plasticity-relevant gene expression. In the first part of the project, we were able to define the impact of the axonal deletion of importin β1 on mouse memory performances. This is an unexpected observation, since the prediction was that importins should be involved in postsynaptic transport from synapse to nucleus in paradigms of behavior and activity regulation. Moreover, we found a presynaptic phenotype resulting from subcellular removal of importin β1 in central neurons in mice. However, we found no evidence for retrograde transport of Jacob in axons. Nonetheless, we could decipher molecular underpinnings of synapse-to-nucleus transport of Jacob and show that Jacob docks a signalosome to CREB that is instrumental for memory consolidation and late-phase LTP in the hippocampus.

Publications

• Synaptic control of DNA methylation involves activity-dependent degradation of DNMT3A1 in the nucleus. Neuropsychopharmacology, 45(12), 2120-2130.
  Bayraktar, Gonca; Yuanxiang, PingAn; Confettura, Alessandro D.; Gomes, Guilherme M.; Raza, Syed A.; Stork, Oliver; Tajima, Shoji; Suetake, Isao; Karpova, Anna; Yildirim, Ferah & Kreutz, Michael R.
  
• Jacob, a Synapto-Nuclear Protein Messenger Linking N-methyl-D-aspartate Receptor Activation to Nuclear Gene Expression. Frontiers in Synaptic Neuroscience, 13.
  Grochowska, Katarzyna M.; Bär, Julia; Gomes, Guilherme M.; Kreutz, Michael R. & Karpova, Anna
  
• Multiomics of synaptic junctions reveals altered lipid metabolism and signaling following environmental enrichment. Cell Reports, 37(1), 109797.
  Borgmeyer, Maximilian; Coman, Cristina; Has, Canan; Schött, Hans-Frieder; Li, Tingting; Westhoff, Philipp; Cheung, Yam F.H.; Hoffmann, Nils; Yuanxiang, PingAn; Behnisch, Thomas; Gomes, Guilherme M.; Dumenieu, Mael; Schweizer, Michaela; Chocholoušková, Michaela; Holčapek, Michal; Mikhaylova, Marina; Kreutz, Michael R. & Ahrends, Robert
  
• The nuclear lamina is a hub for the nuclear function of Jacob. Molecular Brain, 14(1).
  Samer, Sebastian; Raman, Rajeev; Laube, Gregor; Kreutz, Michael R. & Karpova, Anna
  
• One-step purification of tag free and soluble lamin B1 from an E. coli bacterial expression system. Protein Expression and Purification, 193, 106057.
  Raman, Rajeev; Karpova, Anna & Kreutz, Michael R.
  
• The needs of a synapse—How local organelles serve synaptic proteostasis. The EMBO Journal, 41(7).
  Grochowska, Katarzyna M.; Andres‐Alonso, Maria; Karpova, Anna & Kreutz, Michael R.
  
• Integration of nuclear Ca2+ transients and subnuclear protein shuttling provides a novel mechanism for the regulation of CREB-dependent gene expression. Cellular and Molecular Life Sciences, 80(8).
  Karpova, Anna; Samer, Sebastian; Turacak, Rabia; Yuanxiang, PingAn & Kreutz, Michael R.
  
• Jacob‐induced transcriptional inactivation of CREB promotes Aβ‐induced synapse loss in Alzheimer's disease. The EMBO Journal, 42(4).
  Grochowska, Katarzyna M.; Gomes, Guilherme M.; Raman, Rajeev; Kaushik, Rahul; Sosulina, Liudmila; Kaneko, Hiroshi; Oelschlegel, Anja M.; Yuanxiang, PingAn; Reyes‐Resina, Irene; Bayraktar, Gonca; Samer, Sebastian; Spilker, Christina; Woo, Marcel S.; Morawski, Markus; Goldschmidt, Jürgen; Friese, Manuel A.; Rossner, Steffen; Navarro, Gemma; Remy, Stefan ... & Kreutz, Michael R.
  
• Protein transport from pre- and postsynapse to the nucleus: Mechanisms and functional implications. Molecular and Cellular Neuroscience, 125, 103854.
  Andres-Alonso, Maria; Grochowska, Katarzyna M.; Gundelfinger, Eckart D.; Karpova, Anna & Kreutz, Michael R.