Research Focus
Our research focusses on vesicular and non-vesicular membrane transport processes in neuronal and other excitable cells serving a fundamental role in cellular communication. Vesicular carriers transport and secrete biomolecules such as neurotransmitters, hormones and peptides by means of tethering and fusion and are essential entities for Ca2+-evoked exocytosis. In addition to vesicle-based routes, cells communicate through non-vesicular pathways at membrane contact sites formed at interorganelle interfaces. Emerging evidence suggests a profound impact of membrane contact sites in Ca2+-evoked release through modulation of the lipid and ion composition. Accordingly, membrane contact site dysfunction is associated with neurodegenerative diseases and metabolic disorders among others. However, the distinct interplay and spatiotemporal regulation of vesicular and non-vesicular transport in healthy and diseased states remains unresolved.
We aim at elucidating the underlying mechanisms and how these are linked to their membrane-associated ultrastructure by analyzing the molecular machineries steering these processes, and by identifying new candidates and interaction partners involved in neuronal membrane dynamics. Here, we focus on the C2 domain protein family of ferlins, which are membrane-anchored proteins orchestrating Ca2+-sensitive membrane dynamics in auditory synapses and muscle cells. Mutations in these proteins cause hearing impairment (otoferlin), muscular dystrophy (dysferlin and myoferlin) and cancer (myoferlin), but their molecular mechanisms remain largely unresolved. A new research line aims at analyzing the role of tethering and lipid transfer proteins at membrane contact sites.
Methodologically, my group employs bottom-up approaches, studying membrane proteins (recombinant and native) reconstituted into artificial membranes, isolated organelles outside of their native cellular environment from mouse tissue and cultured cells, and “hybrid” vesicles consisting of native organelles fused with artificial vesicles in a protein-dependent manner. These reductionist strategies allow us to precisely control parameters such as the ion and lipid composition, membrane curvature and tension, as well as the presence or absence of drug candidates, thereby enabling the dissection of factors critical for protein function. These approaches are integrated with advanced analytics including biochemical and biophysical methodologies, alongside advanced electron microscopy techniques including single particle cryo electron microscopy and cryo electron tomography, and proteomics analyses.