Forschungsschwerpunkte

Neuronal connectivity is regulated not only during development but also in the adult brain, in response to environmental stimuli. The small GTPase protein Ras is a universal intracellular signaling protein that mediates such mechanisms of brain plasticity through transient activation of downstream protein phosphorylation signaling cascades. We have developed a synRas animal model expressing permanently activated Val12 Ras, selectively in neurons. Using this model we investigate if enhanced neuronal Ras activity is involved in dendritic spine formation, in the regulation of synapse number and their efficiency and in the regulation of neurogenesis in the adult hippocampus. We also analyse the molecular mechanism of Ras-mediated protection against lesion-induced neuronal degeneration especially in models of Parkinson`s disease and mood diseases. Ras-mediated protection of patient-derived cells reprogrammed by appropriate transcription factors are thought to advance future concepts of replacement therapies.
Ras homologue enriched in brain (Rheb) is a protein that carries an amino acid arginine in the critical position 12 corresponding to the activation of Ras. Rheb and its downstream kinase mTOR (target of rapamycin) have evolutionary conserved functions promoting cellular growth and regeneration. However, we show that certain cellular stressors are able to switch this pathway such that Rheb acquires a pro-apototic function. This observation is of importance for the application of rapamycin in clinical settings to prevent cellular growth. Rapamycin may be protective under certain pathological conditions such as cellular models of neuronal degeneration.
Nitric oxide (NO) is a membrane permeable gas that regulates intracellular signalling via guanylate cyclase and enhances Ras activity via nitrosylation of the amino acid cysteine. Here we investigate if there are additional effects of NO by measuring its action on membrane fluidity. A direct non-covalent interaction of NO with lipid membranes could have a major impact on brain development and function in cellular differentiation processes.