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Prof. Dr. Leonhard Möckl

  • Professorship for Nano-optical Imaging
  • Associated Group Leader
  • Room A.3.428
  • Phone +49 9131 7133115
  • Email
  • Head of research group Physical Glycosciences

Leonhard Möckl studied Chemistry and Biochemistry at LMU Munich. He obtained his PhD in 2015 with a thesis on the role of the glycocalyx in membrane protein organization. In 2016, he joined the lab of W.E. Moerner at Stanford University, where he used single-molecule techniques to investigate the glycocalyx and furthermore developed deep-learning based approaches for single-molecule studies. In 2020, he joined the MPL as an independent group leader. Since 2024, he holds the professorship for Nano-optical Imaging at FAU, located at the newly established CITABLE.

In his free time, he loves to read, to play the piano, to hike, and to play volleyball.

2025

Bottom-up investigation of spatiotemporal glycocalyx dynamics with interferometric scattering microscopy

Carla M. Brunner, Lorenz Pietsch, Ingo vom Sondern, Michael Röhrl, Cristian Popov, Marius F.W. Trollmann, Richard W. Taylor, Martin Blessing, Cornelia Holler, et al.

Journal of the American Chemical Society 147 32799-32808 (2025) | Journal | PDF

Over recent decades, the glycocalyx, an extracellular organelle comprised of a multitude of glycolipids, glycoproteins, proteoglycans and glycoRNA, has gained considerable interest in cellular biology. While research in this field has revealed its tremendous importance in evermore aspects of physiological and pathological cellular processes, many of the principles that govern the role of the glycocalyx in these processes on a molecular level are still unknown. In order to unravel the fundamental laws underlying glycocalyx function, new technologies are required that enable the distinction between individual subprocesses within the intricate environment of the glycocalyx. Here, we establish an experimental platform to investigate the dynamics of the glycocalyx at the nanometer and microsecond length and time scales in a bottom-up fashion. We synthesized defined model glycans and installed them on supported lipid bilayers, assembling glycocalyx model systems with tunable properties. By investigating these tunable model systems with interferometric scattering (iSCAT) microscopy, we gain access to the required spatiotemporal resolution. We found a strong correlation between the molecular structure of several investigated model glycans and global dynamics of the system. Our findings are corroborated by atomistic and coarsegrained molecular dynamics simulations. Our results provide the first direct experimental evidence on the relationship between glycan structure, organization, and dynamics, offering a robust and versatile basis for a quantitative understanding of glycocalyx biology and physics at the molecular level.

Treatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein

Benson M. George, Maria Eleftheriou, Eliza Yankova, Jonathan Perr, Peiyuan Chai, Gianluca Nestola, Karim Almahayni, Siân Evans, Aristi Damaskou, et al.

Nature Biotechnology (2025) | Journal | PDF

Immunotherapies for acute myeloid leukemia (AML) and other cancers are limited by a lack of tumor-specific targets. Here we discover that RNA-binding proteins and glycosylated RNAs (glycoRNAs) form precisely organized nanodomains on cancer cell surfaces. We characterize nucleophosmin (NPM1) as an abundant cell surface protein (csNPM1) on a variety of tumor types. With a focus on AML, we observe csNPM1 on blasts and leukemic stem cells but not on normal hematopoietic stem cells. We develop a monoclonal antibody to target csNPM1, which exhibits robust anti-tumor activity in multiple syngeneic and xenograft models of AML, including patient-derived xenografts, without observable toxicity. We find that csNPM1 is expressed in a mutation-agnostic manner on primary AML cells and may therefore offer a general strategy for detecting and treating AML. Surface profiling and in vivo work also demonstrate csNPM1 as a target on solid tumors. Our data suggest that csNPM1 and its neighboring glycoRNA–cell surface RNA-binding protein (csRBP) clusters may serve as an alternative antigen class for therapeutic targeting or cell identification.

RNA binding proteins and glycoRNAs form domains on the cell surface for cell penetrating peptide entry

Jonathan Perr, Andreas Langen, Karim Almahayni, Gianluca Nestola, Peiyuan Chai, Charlotta G. Lebedenko, Regan Volk, Reese M. Caldwell, Malte Spiekermann, et al.

Cell 188 1878-1895 (2025) | Journal

The composition and organization of the cell surface determine how cells interact with their environment. Traditionally, glycosylated transmembrane proteins were thought to be the major constituents of the external surface of the plasma membrane. Here, we provide evidence that a group of RNA-binding proteins (RBPs) is present on the surface of living cells. These cell-surface RBPs (csRBPs) precisely organize into well-defined nanoclusters enriched for multiple RBPs and glycoRNAs, and their clustering can be disrupted by extracellular RNase addition. These glycoRNA-csRBP clusters further serve as sites of cell-surface interaction for the cell-penetrating peptide trans-activator of transcription (TAT). Removal of RNA from the cell surface, or loss of RNA-binding activity by TAT, causes defects in TAT cell internalization. Together, we provide evidence of an expanded view of the cell surface by positioning glycoRNA-csRBP clusters as a regulator of communication between cells and the extracellular environment.

A framework for the simulation of individual glycan coordinates to analyze spatial relationships within the glycocalyx

Sarah Fritsche, Leonhard Möckl

Frontiers in Cell and Developmental Biology 12 (2025) | Journal | PDF

The glycocalyx is a dense and dynamic layer of glycosylated species that covers every cell in the human body. It plays crucial roles in various cellular processes in health and disease, such as cancer immune evasion, cancer immune therapy, blastocyst implantation, and functional attenuation of membrane protein diffusion. In addition, alterations in glycocalyx structure may play an important role in ocular surface diseases, e.g., dry eye disease. Despite the emerging importance of the glycocalyx, various aspects of its functional organization remain elusive to date. A central reason for this elusiveness is the nanoscale dimension of the glycocalyx in conjunction with its high structural complexity, which is not accessible to observation with conventional light microscopy. Recent advances in super-resolution microscopy have enabled resolutions down to the single-digit nanometer range. In order to fully leverage the potential of these novel methods, computational frameworks that allow for contextualization of the resulting experimental data are required. Here, we present a simulation-based approach to analyze spatial relationships of glycan components on the cell membrane based on known geometrical parameters. We focus on sialic acids in this work, but the technique can be adapted to any glycan component of interest. By integrating data from mass spectrometry and quantitative biological studies, these simulations aim to model possible experimental outcomes, which can then be used for further analysis, such as spatial point statistics. Importantly, we include various experimental considerations, such as labeling and detection efficiency. This approach may contribute to establishing a new standard of connection between geometrical and molecular-resolution data in service of advancing our understanding of the functional role of the glycocalyx in biology as well as its clinical potential.

Here you can download Leonhard's CV.

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