News

Brenda Schulman, Ulrich Hartl and Wolfgang Baumeister receive a research grant to study Mechanisms of Parkinsons’s disease.

Brenda Schulman, Ulrich Hartl and Wolfgang Baumeister, all directors at the Max Planck Institute of Biochemistry in Martinsried, Germany have received a research grant to study the mechanisms of Parkinson’s disease from the Aligning Science Across Parkinson’s Initiative, the implementing partner of the Michael J. Fox Foundation for Parkinson’s Research is ASAP’s implementation partner. The research project will be led by Wade Harper, head of the Department of Cell Biology in the Blavatnik Institute at Havard Medical School, USA. Harper and co-investigators from the Max-Panck-Institute of Biochemistry as well as Ruben Fernandez-Busnadiego from the University of Göttingen and Judith Frydman at Stanford University, USA aim to elucidate the molecular aberrations in nerve cells that give rise to the Parkinson’s disease.

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graduationCongratulations on your PhD!


Kira Bartnik
Single-Molecule FRET Studies of Protein Function and Conformational Dynamics -
From DNA Nanotechnology to Viral and Bacterial Infections
RG: Don Lamb

 


 

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Wu, Y., Dal Maschio, M., Kubo, F., and Baier, H.
Neuron, 2020, [Epub ahead of print].
doi: 10.1016/j.neuron.2020.08.027

An Optical Illusion Pinpoints an Essential Circuit Node for Global Motion Processing

Direction-selective (DS) neurons compute the direction of motion in a visual scene. Brain-wide imaging in larval zebrafish has revealed hundreds of DS neurons scattered throughout the brain. However, the exact population that causally drives motion-dependent behaviors-e.g., compensatory eye and body movements-remains largely unknown. To identify the behaviorally relevant population of DS neurons, here we employ the motion aftereffect (MAE), which causes the well-known "waterfall illusion." Together with region-specific optogenetic manipulations and cellular-resolution functional imaging, we found that MAE-responsive neurons represent merely a fraction of the entire population of DS cells in larval zebrafish. They are spatially clustered in a nucleus in the ventral lateral pretectal area and are necessary and sufficient to steer the entire cycle of optokinetic eye movements. Thus, our illusion-based behavioral paradigm, combined with optical imaging and optogenetics, identified key circuit elements of global motion processing in the vertebrate brain.


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Tüshaus, J., Müller, S.A., Kataka, E.S., Zaucha, J., Sebastian Monasor, L., Su, M., Güner, G., Jocher, G., Tahirovic, S., Frishman, D., Simons, M., and Lichtenthaler, S.F.
(IMPRS_LS students are in bold)
EMBO J, 2020, e105693, online ahead of print.
doi: 10.15252/embj.2020105693

An optimized quantitative proteomics method establishes the cell type-resolved mouse brain secretome

To understand how cells communicate in the nervous system, it is essential to define their secretome, which is challenging for primary cells because of large cell numbers being required. Here, we miniaturized secretome analysis by developing the "high-performance secretome protein enrichment with click sugars" (hiSPECS) method. To demonstrate its broad utility, hiSPECS was used to identify the secretory response of brain slices upon LPS-induced neuroinflammation and to establish the cell type-resolved mouse brain secretome resource using primary astrocytes, microglia, neurons, and oligodendrocytes. This resource allowed mapping the cellular origin of CSF proteins and revealed that an unexpectedly high number of secreted proteins in vitro and in vivo are proteolytically cleaved membrane protein ectodomains. Two examples are neuronally secreted ADAM22 and CD200, which we identified as substrates of the Alzheimer-linked protease BACE1. hiSPECS and the brain secretome resource can be widely exploited to systematically study protein secretion and brain function and to identify cell type-specific biomarkers for CNS diseases.


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Agarwal, R., and Duderstadt, K.E.
Nat Commun, 2020, 11, 4714.
doi: 10.1038/s41467-020-18456-y

Multiplex flow magnetic tweezers reveal rare enzymatic events with single molecule precision

The application of forces and torques on the single molecule level has transformed our understanding of the dynamic properties of biomolecules, but rare intermediates have remained difficult to characterize due to limited throughput. Here, we describe a method that provides a 100-fold improvement in the throughput of force spectroscopy measurements with topological control, which enables routine imaging of 50,000 single molecules and a 100 million reaction cycles in parallel. This improvement enables detection of rare events in the life cycle of the cell. As a demonstration, we characterize the supercoiling dynamics and drug-induced DNA break intermediates of topoisomerases. To rapidly quantify distinct classes of dynamic behaviors and rare events, we developed a software platform with an automated feature classification pipeline. The method and software can be readily adapted for studies of a broad range of complex, multistep enzymatic pathways in which rare intermediates have escaped classification due to limited throughput.


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Gehrlach, D.A., Weiand, C., Gaitanos, T.N., Cho, E., Klein, A.S., Hennrich, A.A., Conzelmann, K.K., and Gogolla, N. (IMPRS-LS students are in bold)
Elife, 2020, 9.
doi: 10.7554/eLife.55585

A whole-brain connectivity map of mouse insular cortex

The insular cortex (IC) plays key roles in emotional and regulatory brain functions and is affected across psychiatric diseases. However, the brain-wide connections of the mouse IC have not been comprehensively mapped. Here, we traced the whole-brain inputs and outputs of the mouse IC across its rostro-caudal extent. We employed cell-type-specific monosynaptic rabies virus tracings to characterize afferent connections onto either excitatory or inhibitory IC neurons, and adeno-associated viral tracings to label excitatory efferent axons. While the connectivity between the IC and other cortical regions was highly bidirectional, the IC connectivity with subcortical structures was often unidirectional, revealing prominent cortical-to-subcortical or subcortical-to-cortical pathways. The posterior and medial IC exhibited resembling connectivity patterns, while the anterior IC connectivity was distinct, suggesting two major functional compartments. Our results provide insights into the anatomical architecture of the mouse IC and thus a structural basis to guide investigations into its complex functions.


Peter Krenn from the Department Molecular Medicine (Director Reinhard Fässler) at the Max Planck Institute of Biochemistry has found a new way to attack leukemic stem cells.

Blood – the juice of life Blood supplies complex organisms with nutritive substances, transports metabolic products or messenger substances. Cellular components of blood are erythrocytes responsible for the transport of oxygen and carbon dioxide, thrombocytes responsible for blood coagulation and leukocytes responsible for the immune defense. As each of these blood cells has a limited lifespan, and are massively lost during bleeding or consumed during infections. Hence, they must be continuously replaced, which is ensured by the so-called hematopoietic stem cells in the bone marrow. These cells have the ability to develop into any type of blood cell. Chronic myeloid leukemia In chronic myeloid leukemia, the hematopoietic stem cell undergoes a genetic mutation by recombining chromosome 9 and 22. As a result, gene building blocks fuse that would otherwise not be in contact with each other. The incorrectly assembled chromosome is called Philadelphia chromosome and harbors the construction manual for the so-called BCR-ABL oncogene. This causes the leukemic stem cell to behave selfishly: it divides and multiplies drastically at the expense of healthy blood stem cells.

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graduationCongratulations on your PhD!


Daniel Gehrlach
Anatomical and functional characterization of the mouse insular cortex
RG: Nadine Gogolla

Daniil Markov
Involvement of cerebellar Purkinje cells in adaptive locomotion of larval zebrafish
RG: Ruben Portugues


 

MPIB scientists have contributed to deciphering the 3D structure of the nuclear pore of baker's yeast cells.

Research group leader Boris Pfander and his team from the Max Planck Institute of Biochemistry, together with colleagues from the Max Planck Institute of Biophysics in Frankfurt am Main and the EMBL in Heidelberg, have investigated the 3D structure of nuclear pores in budding yeast (Saccharomyces cerevisiae). Their results, published in Nature, reveal the architecture of the nuclear pore complex in intact cells and broaden our understanding of crucial processes in life.

Nuclear pores are a highly complex assembly of proteins. Hundreds of them are embedded in the double membrane that surrounds and protects the cell’s nucleus. They act as a gateway that regulates the entry and exit of molecules. An important function of nuclear pores is to regulate the export of a molecule called messenger RNA (mRNA) from the nucleus into the surrounding cell – the cytoplasm – where it delivers instructions for the assembly of proteins. Revealing the architecture Now the scientists appreciate better how the nuclear pore works in its native context, how it is maintained and recycled. The study provides a detailed structural description of the three protein rings that make up the nuclear pore, known as the cytoplasmic, nuclear, and inner rings. To show how these rings are arranged in cells, the researchers used a combination of cell biology, computational modelling, and in-cell cryo-electron tomography: an imaging technique, that is used to produce high-resolution 3D views of the molecular landscape inside a cell. This led to fundamental new insights. The scientist found out that the 3D configuration of the cytoplasmic ring accommodates the path of mRNA export.

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Eklund, A.S., Ganji, M., Gavins, G., Seitz, O., and Jungmann, R.
Nano Lett, 2020, [Epub ahead of print].
doi: 10.1021/acs.nanolett.0c02620

Peptide-PAINT Super-Resolution Imaging Using Transient Coiled Coil Interactions

Super-resolution microscopy is transforming research in the life sciences by enabling the visualization of structures and interactions on the nanoscale. DNA-PAINT is a relatively easy-to-implement single-molecule-based technique, which uses the programmable and transient interaction of dye-labeled oligonucleotides with their complements for super-resolution imaging. However, similar to many imaging approaches, it is still hampered by the subpar performance of labeling probes in terms of their large size and limited labeling efficiency. To overcome this, we here translate the programmability and transient binding nature of DNA-PAINT to coiled coil interactions of short peptides and introduce Peptide-PAINT. We benchmark and optimize its binding kinetics in a single-molecule assay and demonstrate its super-resolution capability using self-assembled DNA origami structures. Peptide-PAINT outperforms classical DNA-PAINT in terms of imaging speed and efficiency. Finally, we prove the suitability of Peptide-PAINT for cellular super-resolution imaging by visualizing the microtubule and vimentin network in fixed cells.