Projects

As part of a holistic, translational research concept, the Neurohomeostasis research group investigates the interplay between stress and homeostasis. Our basic and applied research projects are organized into three interconnected branches:

All projects are conducted in either local, national, or international cooperation.

Stress and Autophagy in the Cell

Autophagy is a cellular degradation and recycling process at the core of our research. It serves as a crucial mechanism for removing damaged proteins and organelles, thereby maintaining cellular integrity. We investigate how stress influences autophagy, particularly through modulation of the stress-regulated co-chaperone FKBP51. This interaction provides insights into the body’s adaptive responses to stress and reveals potential therapeutic strategies to enhance cellular and systemic resilience. By extending our research into the field of virology, we explore the dynamic relationship between autophagy and viral infections. This important research direction highlights autophagy’s role as a defense mechanism against viral pathogens. Understanding these processes opens new avenues for antiviral strategies and therapeutic interventions.

Related Publications:

Balsevich G, Häusl AS, Meyer CW, et al. Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function. Nat Commun. 2017;8(1):1725. doi:10.1038/s41467-017-01783-y

Gassen NC, Niemeyer D, Muth D, et al. SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection. Nat Commun. 2019;10(1):5770. doi:10.1038/s41467-019-13659-4

Hoffmann M, Mösbauer K, Hofmann-Winkler H, et al. Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2. Nature. 2020;585(7826):588-590. doi:10.1038/s41586-020-2575-3

Gassen NC, Papies J, Bajaj T, et al. SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals. Nat Commun. 2021;12(1):3818. doi:10.1038/s41467-021-24007-w

Radke J, Meinhardt J, Aschman T, et al. Proteomic and transcriptomic profiling of brainstem, cerebellum and olfactory tissues in early- and late-phase COVID-19. Nat Neurosci. 2024;27(3):409-420. doi:10.1038/s41593-024-01573-y

Martinelli S, Anderzhanova EA, Bajaj T, et al. Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion. Nat Commun. 2021;12(1):4643. doi:10.1038/s41467-021-24810-5

Häusl AS, Bajaj T, Brix LM, et al. Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism. Sci Adv. 2022;8(10):eabi4797. doi:10.1126/sciadv.abi4797

Hartmann J, Bajaj T, Otten J, et al. SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration. Nat Commun. 2024;15(1):2635. doi:10.1038/s41467-024-46953-x

Bajaj T, Ebert T, Dillmann LJ, Sokn C, Gassen NC, Hartmann J. SKArred 2 death: neuroinflammatory breakdown of the hippocampus. Autophagy. 2024;20(11):2581-2583. doi:10.1080/15548627.2024.2373675

Bordes J, Bajaj T, Miranda L, et al. Sex-specific fear acquisition following early life stress is linked to amygdala and hippocampal purine and glutamate metabolism. Commun Biol. 2024;7(1):1684. doi:10.1038/s42003-024-07396-8

Hartmann J, Klengel C, Dillmann LJ, et al. SKA2 enhances stress-related glucocorticoid receptor signaling through FKBP4-FKBP5 interactions in neurons. Proc Natl Acad Sci U S A. 2024;121(52):e2417728121. doi:10.1073/pnas.2417728121

Modulation of Autophagy as a Therapeutic Approach

The aim of our research is not only to gain new insights into fundamental cellular mechanisms, but also to develop innovative therapeutic strategies that can significantly impact the treatment success of stress-related disorders. At the core of our work is the modulation of autophagy. By investigating the signaling pathways of these homeostatic processes, we strive to identify novel therapeutic targets for stress-related conditions. Due to its ability to induce autophagy, the endogenous metabolite spermidine has emerged as a central focus within this project branch. Exploring spermidine and its therapeutic potential is not only of scientific interest but also holds promise for translational medicine. New treatment strategies could, for example, harness autophagy induction to combat disease and promote longevity.

Related Publications:

Gassen NC, Hartmann J, Zannas AS, et al. FKBP51 inhibits GSK3β and augments the effects of distinct psychotropic medications. Mol Psychiatry. 2016;21(2):277-289. doi:10.1038/mp.2015.38

Gassen NC, Fries GR, Zannas AS, et al. Chaperoning epigenetics: FKBP51 decreases the activity of DNMT1 and mediates epigenetic effects of the antidepressant paroxetine. Sci Signal. 2015;8(404):ra119. doi:10.1126/scisignal.aac7695

Wiechmann S, Ruprecht B, Siekmann T, et al. Chemical Phosphoproteomics Sheds New Light on the Targets and Modes of Action of AKT Inhibitors. ACS Chem Biol. 2021;16(4):631-641. doi:10.1021/acschembio.0c00872

Stepan J, Heinz DE, Dethloff F, et al. Hippo-released WWC1 facilitates AMPA receptor regulatory complexes for hippocampal learning. Cell Rep. 2022;41(10):111766. doi:10.1016/j.celrep.2022.111766

Stepan J, Heinz DE, Dethloff F, et al. Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice. Sci Signal. 2024;17(834):eadj6603. doi:10.1126/scisignal.adj6603

Martinelli S, Hafner K, Koedel M, Knauer-Arloth J, Gassen NC, Binder EB. Differential Dynamics and Roles of FKBP51 Isoforms and Their Implications for Targeted Therapies. Int J Mol Sci. 2024;25(22). doi:10.3390/ijms252212318

Hofer SJ, Daskalaki I, Bergmann M, et al. Spermidine is essential for fasting-mediated autophagy and longevity. Nat Cell Biol. 2024;26(9):1571-1584. doi:10.1038/s41556-024-01468-x

Autophagy and Mental Health in Clinical Research

The implementation of human intervention studies has emerged as the third branch of our research group. Although there is substantial evidence for a central role of autophagy in mediating stress responses at the cellular level, few studies have explored the causal relationships between stressors, autophagy, and mental health in humans. Within our interdisciplinary team of clinician scientists and basic researchers, we have developed experimental pipelines to investigate the impact of various stressors on specific molecular parameters in vivo. With the goal of developing rapid, effective lifestyle interventions for the prevention and treatment of mental health disorders, we conduct innovative intervention studies using age- and gender-balanced designs. Our primary aim is to understand how exercise, diet, or high stress levels affect autophagy and how modulating autophagy influences mental health. To this end, we carry out intervention trials involving healthy volunteers as well as patients with mild to moderate depression. Using a wide range of advanced analytical techniques—including metabolomics, proteomics, phosphoproteomics, and transcriptomics—we strive to directly link our findings to metabolic processes and proteostasis.

Registered Studies at ClinicalTrials.gov:

NCT04739852 – An Exploratory Clinical Study on Autophagy During Fasting (AutoFast)
NCT04823806 – An Exploratory Clinical Study on Autophagy and Multi-level Molecular Profiling During Spermidine Supplementation (StressLess)
NCT05144022 – Multi-level Molecular Profiling of High Acute Stress: a Clinical Study (HighStress)
NCT05359744 – Multi-level Molecular Profiling of Peak Performance in Endurance Sports (AutoSport)
NCT06016530 – Multi-level Molecular Profiling of Stress Exposure Under Standardized Food Intake: A Clinical Study (NutriMol)

Cooperation

We rely on a multidisciplinary approach that enriches our research and accelerates innovation. Scientific collaboration with our partners is therefore a central element of our research philosophy. We proudly maintain a network of national and international partnerships. This collaborative effort is essential for addressing the complex questions of biology and demonstrates the synergistic impact of joint scientific endeavors.

Our closest collaborations include:

Jakob Hartmann & Kerry J. Ressler (McLean Hospital, Harvard Medical School, Boston, US)
Raluca Contu & Michał Ślęzak (Łukasiewicz – PORT, Wrocław, Poland)
Frank Madeo & Tobias Eisenberg (Universität Graz, Österreich)
Jens Stepan (Universitätsspital Zürich, Schweiz)
Mathias V. Schmidt (Max Planck Institut für Psychiatrie, München)
Bernhard Kuster (Technische Universität, München)
Jürgen Cox (Max Planck Institut für Biochemie, Martinsried)
Marcel A. Müller (Institut für Virologie, Charité, Berlin)
Marianne B. Müller (Leibnitz Institut für Resilienz Forschung, Universitätsklinik Mainz)
Valentin Stein & Anne Gellner (Uniklinikum Bonn)
Felix Meissner (Uniklinikum Bonn)