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When it comes to recovering from insult, the adult human brain has very little ability to compensate for nerve-cell loss. Biomedical researchers and clinicians are therefore exploring the possibility of using transplanted nerve cells to replace neurons that have been irreparably damaged as a result of trauma or disease. However, it is not clear whether transplanted neurons can be integrated sufficiently, to result in restored function of the lesioned network. Now researchers at the Max Planck Institute of Neurobiology in Martinsried, the Ludwig Maximilians University Munich and the Helmholtz Zentrum München have demonstrated that, in mice, transplanted embryonic nerve cells can indeed be incorporated into an existing network and correctly carry out the tasks of damaged cells originally found in that region.

Neurodegenerative diseases such as Alzheimer's or Parkinson's disease, but also stroke or certain injuries lead to a loss of brain cells. The mammalian brain can replace these cells only in very limited areas, making the loss in most cases a permanent one. The transplantation of young nerve cells into an affected network of patients for example with Parkinson's disease, allow for the possibility of a medical improvement of clinical symptoms. However, if the nerve cells transplanted in such studies help to overcome existing network gaps or whether they actually replace the lost cells, remained unknown.

In the joint study, researchers of the Max Planck Institute of Neurobiology, the Ludwig Maximilians University Munich and the Helmholtz Zentrum München have specifically asked whether transplanted embryonic nerve cells can functionally integrate into the visual cortex of adult mice. The study was supported by the center grant (SFB) 870 of the German Research Foundation (DFG). “This brain region is ideal for such experiments,” says Magdalena Götz, joint leader of the study together with Mark Hübener, who continues to explain: “By now, we know so much about the functions of the nerve cells in the visual cortex and the connections between them that we can readily assess whether the new nerve cells actually perform the tasks normally carried out by the network.”

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Park, D.I., Dournes, C., Sillaber, I., Uhr, M., Asara, J.M., Gassen, N.C., Rein, T., Ising, M., Webhofer, C., Filiou, M.D., Muller, M.B., and Turck, C.W.
Sci Rep, 2016, 6 , 35317.

Purine and pyrimidine metabolism: Convergent evidence on chronic antidepressant treatment response in mice and humans.

Selective Serotonin Reuptake Inhibitors (SSRIs) are commonly used drugs for the treatment of psychiatric diseases including major depressive disorder (MDD). For unknown reasons a substantial number of patients do not show any improvement during or after SSRI treatment. We treated DBA/2J mice for 28 days with paroxetine and assessed their behavioral response with the forced swim test (FST). Paroxetine-treated long-time floating (PLF) and paroxetine-treated short-time floating (PSF) groups were stratified as proxies for drug non-responder and responder mice, respectively. Proteomics and metabolomics profiles of PLF and PSF groups were acquired for the hippocampus and plasma to identify molecular pathways and biosignatures that stratify paroxetine-treated mouse sub-groups. The critical role of purine and pyrimidine metabolisms for chronic paroxetine treatment response in the mouse was further corroborated by pathway protein expression differences in both mice and patients that underwent chronic antidepressant treatment. The integrated -omics data indicate purine and pyrimidine metabolism pathway activity differences between PLF and PSF mice. Furthermore, the pathway protein levels in peripheral specimens strongly correlated with the antidepressant treatment response in patients. Our results suggest that chronic SSRI treatment differentially affects purine and pyrimidine metabolisms, which may explain the heterogeneous antidepressant treatment response and represents a potential biosignature.


 

Before a cell divides, it must first handle a large-scale project: Its entire genetic material has to be duplicated so that each of the two daughter cells is equipped with a full copy after cell division. As errors in this DNA replication could lead to the death of the cell, the process is rigorously controlled. It takes place in two phases. Researchers at the Max Planck Institute of Biochemistry in Martinsried have now revealed in the journal Cell Reports that these two phases are strictly separated from one another by breaks, thereby preventing errors in the DNA replication.

Elbphilharmonie, Berlin Airport, Stuttgart 21 – large-scale projects are frequently susceptible to errors and these are generally very cost-intensive. A cell’s most important large-scale project is the replication of its DNA, i.e. the complete duplication of its genetic material. Here, errors such as the inadvertent multiplication of a DNA sequence can change the structure of the chromosomes. This can lead to cell death or, in the case of multi-cellular organisms such as humans, to the development of cancer. For this highly important project, the cell increases its success rate by dividing the process of DNA replication into a planning phase, known as the “licensing” phase, and an implementation phase, known as the “firing” phase. The two phases follow in sequence. Boris Pfander, head of the “DNA Replication and Genome Integrity” research group, and his team have demonstrated that the baker’s yeast S. cerevisiae separates the timing of these phases from one another and that the Sld2 protein plays an important role in this regulation. “A crucial factor in the success of the DNA duplication project is, on the one hand, that project planning is completed before the building work begins, but also that no new plans are made while the actual building work is being carried out,” Pfander explains.

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The so-called Holliday structure has nothing to do with holidays or vacation, but is rather a term that describes a complex crossover of similar DNA strings. Researcher Robin Holliday proposed this structure of genetic information in the 1960s. It occurs in DNA repair processes in our cells or during the formation of egg and sperm cells when paternal and maternal genetic information are combined. As reported by the journal eLife, scientists from the Max Planck Institute of Biochemistry in Martinsried have decoded the structure of the GEN1 protein that can undo this crossover, much like a molecular master tailor, by cutting the DNA with the highest precision in the correct place.

Our genetic information is stored in every cell of the body in a DNA double-strand molecule. These can be damaged by chemicals and ultraviolet light, which can in turn lead to breakages in the DNA strings. Many different repair mechanisms have been developed over the course of evolution to repair DNA damage and thereby ensure the survival of various organisms.

To understand the individual repair steps in the cells, Christian Biertümpfel, who leads the Molecular Mechanisms of DNA Repair Research Group, together with his team examined the molecular structure of the GEN1 protein. GEN1 plays an important role in the repair of DNA double-strand breaks. The repair involves a complex crossover of very similar DNA sections, which enables the faulty area to be repaired. The Holliday structure that emerges is then resolved again by GEN1 at the end of the repair process.

“With the aid of X-ray diffraction analysis, we were able to look at the positions of the individual amino acids, which are the basic building blocks of proteins. This allowed us to draw conclusions as to the exact structure and function of GEN1. We can now show that GEN1 works much like a molecular master tailor, inserting precisely symmetric cuts into the Holliday structure of the DNA”, explains Biertümpfel. “What is particularly notable is that GEN1 has a so-called chromodomain, which acts like a tailor’s straightedge. The chromodomain brings the DNA to be cut into the optimum position and increases the efficiency of GEN1”.

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Tobias Bonhoeffer appointed advisor of Chan Zuckerberg Science

In December 2015, Facebook founder Mark Zuckerberg and his wife Priscilla Chan announced their plan to put 99% percent of their Facebook shares, worth about 45 billion dollars, into a new project focusing on the improvement of human potential and the promotion of equality. After an initial focus on education, the initiative has now announced its second focal point: the promotion of basic science research with the goal of curing, preventing or managing all disease by the end of this century. This new project, led by neuroscientist Cori Bargmann, was announced in San Francisco yesterday. In addition to the President, the two founders also introduced the scientists who will help build this initiative in the future. The panel of experts also includes one German researcher: Tobias Bonhoeffer, Director at the Max Planck Institute of Neubiology.

Shortly after the birth of their daughter Maxima Chan Zuckerberg, the couple set up the Chan Zuckerberg Initiative, stating they wished to see their daughter grow up in a world in which it was possible to cure diseases, personalize learning, and connect people. At a press conference on the Mission Bay campus of the University of California in San Francisco yesterday, Chan and Zuckerberg announced the second cornerstone of the initiative: 'Chan Zuckerberg Science'.

Over the past few months, the paediatrician Chan and Facebook founder Zuckerberg had met with numerous scientists, engineers, and other experts. This convinced them of the importance to invest into basic research to achieve much needed scientific progress essential for combating diseases. As a result, they decided to set up "Chan Zuckerberg Science (CZS)". The work of the initiative will have three core elements: More and better cooperation of scientists and engineers, the development of new methods and technologies, and educating the general public about the benefits of scientific discovery with the result of a much more general support and willingness to donate to science.

The only European member of the Scientific Advisory Board is Max Planck Director Tobias Bonhoeffer from Martinsried. "I am truly thrilled to be part of this exciting initiative. I am convinced that CZS can provide a powerful new impetus for imaginative and forward-looking science in the biomedical arena", was his first reaction. "It is a great pleasure and honor for me to have been appointed as advisor," said Bonhoeffer, who had been in contact with Chan and Zuckerberg since their visit to Berlin earlier this year. Being involved in major science policy decisions is however nothing new for the 56-year-old neurobiologist Tobias Bonhoeffer. In his capacity as chairman of the Biology and Medicine Section of the Max Planck Society (2008 - 2011) and as a Governor of the Wellcome Trust, one of the world's largest charities, he has provided guidance and expertise to many decision-making bodies.

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Changes in gene activity are fundamental to many neuropsychiatric disorders. However, the nature of the genes affected, the time and place in which these changes occur, or the impact of these changes on nerve cells, remain largely unknown. One of the reasons for this ignorance is the inability to tag individual genes and their products without disrupting normal cell functions. An international team from the Max Planck Institute of Neurobiology, the University of Birmingham, the Wigner Institute in Budapest and Femtonics Ltd. now aim to close this gap in methodology. The European Union supports the project with a Horizon 2020 grant, worth more than four million Euros.

Many diseases also have a genetic component. For example, gene mutations can lead to the development of cancer or psychiatric disorders such as schizophrenia, depression or autism. Most of these diseases seem to be caused not by a single mutation but are rather the result of the interplay of dozens, maybe even hundreds of altered gene functions. It would therefore be of great benefit for the investigation, diagnosis and therapy of these illnesses, to identify the affected genes and monitor their activity in the brain of the living organism.

An interdisciplinary team around Herwig Baier from the Max Planck Institute of Neurobiology, Attila Sik from the University of Birmingham, Miklós Veres from the Wigner Institute and the microscope developers at Femtonics Ltd. aim to develop such a method. (more)

 


 

Ephrins (blue) and Ephs (red) form complexes (yellow) at cell contact points.

When cells grow and divide, they come into contact with other cells. This happens not only during development and regeneration and after injury, but also during cancer growth and the formation of metastases. When cells come into contact with each other in this way, information is exchanged by proteins, which are embedded in the cell membranes and form tight lock-and-key complexes with each other. These connections must be severed if the cells want to transmit a repulsion signal. It appears that the fastest way to do this is for the cells to engulf the protein complex from the membrane of the neighbouring cell. Scientists from the Max Planck Institute of Neurobiology in Martinsried have now identified the molecules that control this process.

Development is an extremely rapid process. Increasing numbers of cells are formed which must find their correct position in the body, clearly demarcate themselves from each other to form tissue, or – as is the case in the nervous system – establish contact with partner cells in remote locations. “The crowding is accompanied by orderly pushing and shoving,” says Rüdiger Klein, whose Department at the Max Planck Institute of Neurobiology studies how cells get their bearings. “A popular way for one cell to show another which direction to take is for it to repel the other cell following brief contact.” According to the scientists’ observations, the cells do not exactly treat each other with kid gloves and even go so far as to engulf entire pieces from the membranes of other cells. More

 


 

Kank2 expression pattern

Tissue are composed of cells and their surrounding extracellular matrix. During embryonic development, wound healing and cancer metastasis, cells move within tissues. How they do it, is a highly relevant scientific and medical question. Now, researcher at the Max Planck Institute of Biochemistry in Martinsried found a new molecule that regulates the speed of cell migration. Kank2, the newly discovered protein, diminishes the force transmission between cells and extracellular matrix. Thereby the cells find less grip on the ground and move slower.

In tissue, cells are embedded within the extracellular matrix, a meshwork of different protein assemblies. Integrins are anchor proteins on the cell surface, which on the one hand enable cells to adhere to the extracellular matrix, and on the other hand connect to the actin cytoskeleton inside the cells. Hence, integrin-mediated adhesion points transmit mechanical force generated by the contractile cytoskeleton to the extracellular matrix, which is needed for cell migration. The stronger integrin-based adhesions are pulled by mechanical force, the tighter they are anchored on the extracellular matrix. More

 


 

The adult brain has learned to calculate an image of its environment from sensory information. If the input signals change, however, even the adult brain is able to adapt − and, ideally, to return to its original activity patterns once the perturbation has ceased. Scientists at the Max Planck Institute of Neurobiology in Martinsried have now shown in mice that this ability is due to the properties of individual neurons. Their findings demonstrate that individual cells adjust strongly to changes in the environment but after the environment returns to its original state it is again the individual neurons which reassume their initial response properties. This could explain why despite substantial plasticity the perception in the adult brain is rather stable and why the brain does not have to continuously relearn everything.

Everything we know about our environment is based on calculations in our brain. Whereas a child's brain first has to learn the rules that govern the environment, the adult brain knows what to expect and, for the most part, processes environmental stimuli in a stable manner. Yet even the adult brain is able to respond to changes, to form new memories and to learn. Research in recent years has shown that changes to the connections between neurons form the basis of this plasticity. But, how can the brain continually change its connections and learn new things without jeopardizing its stable representation of the environment? Neurobiologists in the Department of Tobias Bonhoeffer in Martinsried have now addressed this fundamental question and looked at the interplay between plasticity and stability.

The scientists studied the stability of the processing of sensations in the visual cortex of the mouse. It has been known for about 50 years that when one eye is temporarily closed, the region of the brain responsive to that eye increasingly becomes responsive to signals from the other eye that is still open. This insight has been important to optimize the use of eye patches in children with a squint. “Thanks to new genetically encoded indicators, it has recently become possible to observe reliably the activity of individual neurons over long periods of time,” says Tobias Rose, the lead author of the study. “With a few additional improvements, we were able to show for the first time what happens in the brain on the single-cell level when such environmental changes occur.”

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F.-Ulrich Hartl, director at the Max Planck Institute of Biochemistry, will receive, together with Arthur L. Horwich and Susan L. Lindquist, this year’s Albany Medical Center Prize. The Albany Medical and Research Prize is endowed with $ 500,000 (450,000 €) and is one of America’s most distinguished Prizes in Medicine. The three awardees were honored for their fundamental and complementary discoveries related to the mechanism of protein folding. The prize will be awarded on September 28 in Albany, NY, USA.

Proteins are small molecular machines within each cell that perform a wide variety of essential tasks. To carry out their critical functions, newly produced immature chain-like proteins have to fold into specific, three-dimensional structures. In the 1980s F.-Ulrich Hartl and Arthur L. Horwich proved that proteins do not fold spontaneously, as had previously been thought. Rather, they need assistants in their folding process, so called chaperones. Hartl and Horwich discovered that certain chaperones function as cage-like ‘folding machines’, offering newly synthesized proteins a protected environment, which allows them to fold properly and adopt their appropriate functional structures. more