Intracellular membranes specialized for distinct functions compartmentalize the cytoplasm of eukaryotic cells. These compartments are interconnected by membrane traffic. We study mechanisms underlying membrane dynamics, with emphasis on their roles in neuronal function and neurotransmission in particular.
An important focus of our research are the membrane traffic reactions underlying the release of fast-acting neurotransmitters at synapses. Neurotransmitters are stored in small “synaptic” vesicles that deliver their content into the synaptic space by fusion with the outer membrane (plasma membrane) of the cell (exocytosis) and are rapidly reformed locally by inward budding from the presynaptic plasma membrane (endocytosis). Studies of the biogenesis and traffic of these vesicles are key to understand synaptic transmission. In addition, these studies are of great relevance towards the elucidation of general mechanisms involved in the secretory and endocytic pathways in all cells. For example, our work on synaptic vesicle endocytosis demonstrating the role of BAR domain-containing proteins and phosphoinositide metabolism in coordinating curvature acquisition with modifications of membrane properties had broad implications in the field of membrane transport.
Phosphoinositides are the lipids that result from the phosphorylation of phosphatidylinositol at the 3,4 and 5 position. Our studies of these lipids, initially at synapses, have converged with studies of other labs in establishing the concept that they are key determinants of membrane identity. The 7 phosphoinositides are heterogeneously distributed within cells and their differentially phosphorylated head groups mediate interactions that occur at membrane interfaces with impact on a broad variety of cell functions. Ongoing projects address mechanisms in the control of PI4P and PI(4,5)P2 at the plasma membrane and of phosphoinositide dephosphorylation cascades that regulate traffic in the endocytic pathway.
A new interest of the lab is the role of membrane contact sites not leading to membrane fusion. We are particularly interested in the role of such contacts in lipid exchanges between membranes, a process thought to play a key role in maintaining the appropriate lipid composition of different membranes. Most membrane phospholipids are synthesized in the ER. Vesicular transport (the transport that involves membrane budding and membrane fusion reactions) plays an important role in delivering newly synthesized lipids to other membranes. Growing evidence however, indicates that direct lipid transfer also occurs at contacts of the ER with other membranes. Research of our lab in this area includes studies of the extended-synaptotagmins, which we have shown to function as tethers between the ER and the plasma membrane with putative lipid transport functions. It also includes studies of VAP, a protein that functions as an anchor in the ER membrane for lipid transport proteins.
Disruption of many of the physiological processes that we investigate in our lab lead to human disease. We build on our basic cell biological work to learn about disease mechanisms, with a special focus on neurodegenerative diseases, such as Alzheimer, Parkinson and ALS. We also focus on disorders resulting from mutations in phosphoinositide metabolizing enzymes.
In our research we use a variety of complementary approaches, including biochemical and structural studies, cell-free systems, dynamic light microscopy imaging of live cells, super-resolution microscopy methods, and mouse genetics.