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Synaptic Membrane Remodeling
NeuroCure Excellence Cluster Project: Molecular machineries shaping synaptic membrane dynamics in health and disease
During our lifetime neurons undergo extensive membrane remodeling: starting from neurodevelopment and the growth of axons and dendrites, through synapse formation followed by selective pruning, during sustained neurotransmission, and, finally, during learning and memory formation. These complex events have to be orchestrated by elaborate signaling cascades, and locally specialized membrane remodeling machineries that are able to couple local intracellular scaffolds (like at the presynaptic active zone or the postsynaptic density) to membrane shape, trafficking organelles, and to the cytoskeleton.
We are interested in uncovering these membrane remodeling mechanisms, in particular focusing on a BAR domain protein family, whose members are capable of shaping membranes and also link to the cytoskeleton as well as membrane trafficking regulation. We use cultured neurons (human, obtained from induced pluripotent stem cells - iPSCs, and also of murine origin) as well as bottom-up approaches with purified proteins and model membranes such as liposomes or giant unilamellar vesicles (GUVs); thereby, we approach the membrane remodeling questions from a more cell biology and neuron physiology perspective as well as from the biophysics point of view. To answer our questions we utilize techniques such as genome editing (CRISPR), super-resolution microscopy, fluorescence spectroscopy, and mass spectrometry (interactomics).
Dr. Agata Witkowska has been working in Professor Volker Haucke’s group since 2019. Thanks to a grant from the NeuroCure Excellence Cluster, the neuroscientist and biophysicist is now leading her own project.
A grant from the NeuroCure Excellence Cluster is a great recognition. What exactly are you researching, Dr. Witkowska?
Witkowska: The grant of 240,000 euros has enabled me to lead my own project with three staff members for the first time. It is designed to last two years and is called "Molecular machineries shaping synaptic membrane dynamics in health and disease". The background is that neurons, or nerve cells, undergo extensive membrane remodeling throughout our lives – from neurodevelopment through synapse formation, and including learning and memory formation. The local shaping of membranes at synapses is also crucial for signal transmission between neurons. We aim to better understand these shaping mechanisms.
Have you discovered anything yet?
Witkowska: My NeuroCure project only started at the beginning of the year, but we have already identified four very interesting protein candidates that are important for neurotransmission at synapses and whose mutations are demonstrably associated with neurological disorders. We are currently investigating how these proteins behave in functioning synapses and what interaction partners they have.
How are you approaching this?
Witkowska: We work with cultured human neurons that we grow in a dish, as well as with model membrane systems and isolated proteins. We use various techniques available at the FMP, from high-resolution microscopy such as STED to mass spectrometry.
You studied biotechnology and earned a PhD in molecular biology. How did you get into neuroscience?
Witkowska: The functioning of our brain has always fascinated me. There is still so infinitely much to explore. We do not know the molecular mechanisms behind many neuroscientific phenomena. With my current and future research, I hope to contribute to understanding brain function at the molecular level. This, of course, also implies the desire to lay the groundwork for uncovering pathological mechanisms in neurological diseases – and thereby perhaps even paving the way for new treatment options. I feel it is a great privilege to be able to pursue my research interests in Volker Haucke’s department. It is simply fantastic to work in such a stimulating environment and to share the joy of exciting discoveries with my wonderful colleagues from my NeuroCure project group.
The interview was conducted by Beatrice Hamberger
Students and interns:
Leonie Rommel (MSc student) from August 2023
Milena Roth (MSc student) from September 2024
Alumni: Iva Marinova, Tim Berneiser, Stephanie Himpich, Felix Fritz, Frieda Roessler, Franziska Budig, Linda Drewicke, Sudeeksha Tyagi
© Silke Oßwald
© Silke Oßwald
© Silke Oßwald
The Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) is part of the Forschungsverbund Berlin e.V. (FVB), which legally represents seven non-university research institutes - members of the Leibniz Association - in Berlin.
Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10,
13125 Berlin, Germany
