The cerebral cortex is where we learn and think, form impressions of our environment, control conscious behaviour, and store memories. According to the textbooks, the upstream regions of the brain like the thalamus only contribute to these processes by forwarding information from the sensory organs to the corresponding regions of the cerebral cortex and filtering the information, if necessary. Scientists from the Max Planck Institute of Neurobiology have now shown that the textbook account will have to be revised in part. In the mouse brain, at least, the thalamus appears to play a considerably more active role in visual processing in the context of learning than was previously assumed.

A young brain has much to learn – including how it should interpret information from both eyes and collate it into a meaningful image of the environment. Hence, the cells in the visual cortex establish connections with each other during brain development to enable the optimum processing of visual environmental stimuli. In some cases, however, the signals from one eye do not correspond with those from the other eye, for example in children with strabismus. This can result in the incorrect “wiring” of the eyes to the cerebral cortex. The resulting visual weakness can often be corrected by temporarily covering the dominant eye. If this is done during the critical phase for the development of visual processing, the cells alter their connections, and the brain area responsible for the dominant eye receives signals from the uncovered, weaker eye.

The brain can thus learn to process the visual information differently – an insight that is applied successfully through the use of eye patches in children with strabismus. These well-researched processes in the visual cortex have also been used for many years as a model for the study of learning mechanisms in the cerebral cortex based on the example of the mouse brain.

When scientists from Tobias Bonhoeffer’s department examined the activity of neurons from upstream brain areas, in particular the thalamus, during a temporary closure of the eye, they made an astonishing discovery: these cells did not simply relay information from the eyes to the cerebral cortex but also altered their signals in response to the eye closure. “This was completely unexpected, as it has been believed for over 50 years that the thalamus only forwards information and is not actively involved in learning processes,” reports Tobias Rose, leader of the study.

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Weckmann, K., Deery, M.J., Howard, J.A., Feret, R., Asara, J.M., Dethloff, F., Filiou, M.D., Iannace, J., Labermaier, C., Maccarrone, G., Webhofer, C., Teplytska, L., Lilley, K., Muller, M.B., and Turck, C.W.
Sci Rep, 2017, 7, 15788.

Ketamine's antidepressant effect is mediated by energy metabolism and antioxidant defense system.

Fewer than 50% of all patients with major depressive disorder (MDD) treated with currently available antidepressants (ADs) show full remission. Moreover, about one third of the patients suffering from MDD does not respond to conventional ADs and develop treatment-resistant depression (TRD). Ketamine, a non-competitive, voltage-dependent N-Methyl-D-aspartate receptor (NMDAR) antagonist, has been shown to have a rapid antidepressant effect, especially in patients suffering from TRD. Hippocampi of ketamine-treated mice were analysed by metabolome and proteome profiling to delineate ketamine treatment-affected molecular pathways and biosignatures. Our data implicate mitochondrial energy metabolism and the antioxidant defense system as downstream effectors of the ketamine response. Specifically, ketamine tended to downregulate the adenosine triphosphate (ATP)/adenosine diphosphate (ADP) metabolite ratio which strongly correlated with forced swim test (FST) floating time. Furthermore, we found increased levels of enzymes that are part of the ‘oxidative phosphorylation’ (OXPHOS) pathway. Our study also suggests that ketamine causes less protein damage by rapidly decreasing reactive oxygen species (ROS) production and lend further support to the hypothesis that mitochondria have a critical role for mediating antidepressant action including the rapid ketamine response.


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Balsevich, G., Hausl, A.S., Meyer, C.W., Karamihalev, S., Feng, X., Pohlmann, M.L., Dournes, C., Uribe-Marino, A., Santarelli, S., Labermaier, C., Hafner, K., Mao, T., Breitsamer, M., Theodoropoulou, M., Namendorf, C., Uhr, M., Paez-Pereda, M., Winter, G., Hausch, F., Chen, A., Tschop, M.H., Rein, T., Gassen, N.C., and Schmidt, M.V.
Nat Commun, 2017, 8, 1725.

Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function.

The co-chaperone FKBP5 is a stress-responsive protein-regulating stress reactivity, and its genetic variants are associated with T2D related traits and other stress-related disorders. Here we show that FKBP51 plays a role in energy and glucose homeostasis. Fkbp5 knockout (51KO) mice are protected from high-fat diet-induced weight gain, show improved glucose tolerance and increased insulin signaling in skeletal muscle. Chronic treatment with a novel FKBP51 antagonist, SAFit2, recapitulates the effects of FKBP51 deletion on both body weight regulation and glucose tolerance. Using shorter SAFit2 treatment, we show that glucose tolerance improvement precedes the reduction in body weight. Mechanistically, we identify a novel association between FKBP51 and AS160, a substrate of AKT2 that is involved in glucose uptake. FKBP51 antagonism increases the phosphorylation of AS160, increases glucose transporter 4 expression at the plasma membrane, and ultimately enhances glucose uptake in skeletal myotubes. We propose FKBP51 as a mediator between stress and T2D development, and potential target for therapeutic approaches.


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Thoma V., Kobayashi K. and Tanimoto H.
eNeuro 4, 2017

The Role of the Gustatory System in the Coordination of Feeding

To survive, all animals must find, inspect and ingest food. Behavioral coordination and control of feeding is therefore a challenge that animals must face. Here, we focus on how the gustatory system guides the precise execution of behavioral sequences that promote ingestion and suppresses competing behaviors. We summarize principles learnt from Drosophila, where underlying sensory neuronal mechanisms are illustrated in great detail. Moreover, we compare these principles with findings in other animals, where such coordination plays prominent roles. These examples suggest that the use of gustatory information for feeding coordination has an ancient origin and is prevalent throughout the animal kingdom.


Atlas of the Heart - A healthy heart beats about two billion times during a lifetime – thanks to the interplay of more than 10,000 proteins. Researcher from the Max Planck Institute of Biochemistry (MPIB) and the German Heart Centre at the Technical University of Munich (TUM) have now determined which and how many individual proteins are present in each type of cell that occurs in the heart. In doing so, they compiled the first atlas of the healthy human heart, known as the cardiac proteome. The atlas will make it easier to identify differences between healthy and diseased hearts in future.

Proteins are the molecular machines of cells, in which they perform a range of functions. They are produced by the cells based on blueprints stored in their DNA. Changes occurring at the DNA or protein level can lead to disorders. For such changes to be recognized as underlying causes of heart disease, it is important to know precisely which proteins are present in the healthy heart and in what quantities.

Protein map of the heart
The first such protein atlas of the heart was recently published in Nature Communications by a research team from Munich. The scientists determined the protein profile of cells in all the regions of the heart, such as heart valves, cardiac chambers and major blood vessels. In addition, they investigated the protein composition in three different cell types of the heart: the cardiac fibroblasts, the smooth muscle cells and the endothelial cells. In this way the researchers were able to map the distribution of proteins in the various regions of the heart. Using mass spectrometry, they identified nearly 11,000 different proteins throughout the heart.

Previous studies had focussed for the most part only on individual cell types, or they used tissue from diseased hearts. "This approach has two problems," says Sophia Doll of the MPIB and lead author of the study. "First, the results did not give a full picture of the heart across all its regions and tissues; and second, comparative data on healthy hearts were often missing. Our study has eliminated both problems. Now the data can be used as a reference for future studies."

"Looking at the protein atlas of the human heart, you can see that all healthy hearts work in a very similar manner. We measured similar protein compositions in all the regions with few differences between them," says Sophia Doll. We were also surprised to find that the right and left halves of the heart are similar, despite having quite different functions: the right half pumps oxygen-poor blood to the lungs, while the left half pumps oxygen-rich blood from the lungs to the body.

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Choi J, Bachmann AL, Tauscher K, Benda C, Fierz B, Müller J.
Nat Struct Mol Biol, 2017, [Epub ahead of print].
doi: 10.1038/nsmb.3488

DNA binding by PHF1 prolongs PRC2 residence time on chromatin and thereby promotes H3K27 methylation.

Polycomb repressive complex 2 (PRC2) trimethylates histone H3 at lysine 27 to mark genes for repression. We measured the dynamics of PRC2 binding on recombinant chromatin and free DNA at the single-molecule level using total internal reflection fluorescence (TIRF) microscopy. PRC2 preferentially binds free DNA with multisecond residence time and midnanomolar affinity. PHF1, a PRC2 accessory protein of the Polycomblike family, extends PRC2 residence time on DNA and chromatin. Crystallographic and functional studies reveal that Polycomblike proteins contain a winged-helix domain that binds DNA in a sequence-nonspecific fashion. DNA binding by this winged-helix domain accounts for the prolonged residence time of PHF1-PRC2 on chromatin and makes it a more efficient H3K27 methyltranferase than PRC2 alone. Together, these studies establish that interactions with DNA provide the predominant binding affinity of PRC2 for chromatin. Moreover, they reveal the molecular basis for how Polycomblike proteins stabilize PRC2 on chromatin and stimulate its activity.


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Karg E, Smets M, Ryan J, Forné I, Qin W, Mulholland CB, Kalideris G, Imhof A, Bultmann S, Leonhardt H.
J Mol Biol, 2017, [Epub ahead of print].
doi: 10.1016/j.jmb.2017.10.014

Ubiquitome analysis reveals PCNA-associated factor 15 (PAF15) as a specific ubiquitination target of UHRF1 in embryonic stem cells.

Ubiquitination is a multifunctional posttranslational modification controlling the activity, subcellular localization and stability of proteins. The E3 ubiquitin ligase UHRF1 is an essential epigenetic factor that recognizes repressive histone marks as well as hemi-methylated DNA and recruits DNMT1. To explore enzymatic functions of UHRF1 beyond epigenetic regulation we conducted a comprehensive screen in mouse embryonic stem cells to identify novel ubiquitination targets of UHRF1 and its paralogue UHRF2. We found differentially ubiquitinated peptides associated with a variety of biological processes such as transcriptional regulation and DNA damage response. Most prominently, we identified PCNA-associated factor 15 (PAF15, also known as Pclaf, Ns5atp9, KIAA0101 and OEATC-1) as a specific ubiquitination target of UHRF1. Although the function of PAF15 ubiquitination in translesion DNA synthesis (TLS) is well characterized, the respective E3 ligase had been unknown. We could show that UHRF1 ubiquitinates PAF15 at Lys 15 and Lys 24 and promotes its binding to PCNA during late S-phase. In summary, we identified novel ubiquitination targets that link UHRF1 to transcriptional regulation and DNA damage response.


A common feature of neurodegenerative diseases such as Alzheimer's, Parkinson's or Huntington's disease are deposits of aggregated proteins in the patient's cells that cause damage to cellular functions. Scientists at the Max Planck Institute of Biochemistry and Ludwig-Maximilians-Universität in Munich report that, even in normal cells, aberrant aggregation-prone proteins are continually produced due to partial failure of the respiratory system. Unless they are removed by degradation, aggregates accumulate preferentially in the mitochondria, the cellular power plants, ultimately blocking energy production. In order to get rid of these toxic aggregates, cells have developed an elaborate protein quality control system.

Misfolded proteins made from defective blueprints are often sticky and clump together. Accumulation of such faulty proteins is known to contribute to the progression of several diseases. Therefore, cells have internal quality control mechanisms that detect and rapidly destroy faulty proteins. Proteins are produced by ribosomes, and misfolding can occur if they stall while decoding a damaged template. If the necessary ribosome-associated quality control machinery (RQC) does not function properly, defective proteins accumulate and form toxic aggregates in the cytoplasm of the cells. A previous study reported that this aggregation mechanism is mediated by so-called CAT-tails – C-terminal alanine-threonine sequences that are added to the defective proteins. So far, studies have focused on how the RQC recognizes and clears blocked ribosomes in the cytosol. The collaborating groups at the Max Planck Institute of Biochemistry and the university have now investigated the clearance of ribosome-blocked proteins destined for the mitochondria.

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Geyer PE, Holdt LM, Teupser D, Mann M.
Mol Syst Biol 2017, 13, 942.
doi: 10.15252/msb.20156297

Revisiting biomarker discovery by plasma proteomics.

Clinical analysis of blood is the most widespread diagnostic procedure in medicine, and blood biomarkers are used to categorize patients and to support treatment decisions. However, existing biomarkers are far from comprehensive and often lack specificity and new ones are being developed at a very slow rate. As described in this review, mass spectrometry (MS)-based proteomics has become a powerful technology in biological research and it is now poised to allow the characterization of the plasma proteome in great depth. Previous "triangular strategies" aimed at discovering single biomarker candidates in small cohorts, followed by classical immunoassays in much larger validation cohorts. We propose a "rectangular" plasma proteome profiling strategy, in which the proteome patterns of large cohorts are correlated with their phenotypes in health and disease. Translating such concepts into clinical practice will require restructuring several aspects of diagnostic decision-making, and we discuss some first steps in this direction.


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Pasalic D, Weber B, Giannone C, Anelli T, Müller R, Fagioli C, Felkl M, John C, Mossuto MF, Becker CFW, Sitia R, Buchner J.
Proc Natl Acad Sci USA 2017, [Epub ahead of print].
doi: 10.1073/pnas.1701797114

A peptide extension dictates IgM assembly.

Professional secretory cells can produce large amounts of high-quality complex molecules, including IgM antibodies. Owing to their multivalency, polymeric IgM antibodies provide an efficient first-line of defense against pathogens. To decipher the mechanisms of IgM assembly, we investigated its biosynthesis in living cells and faithfully reconstituted the underlying processes in vitro. We find that a conserved peptide extension at the C-terminal end of the IgM heavy (Ig-μ) chains, termed the tailpiece, is necessary and sufficient to establish the correct geometry. Alanine scanning revealed that hydrophobic amino acids in the first half of the tailpiece contain essential information for generating the correct topology. Assembly is triggered by the formation of a disulfide bond linking two tailpieces. This induces conformational changes in the tailpiece and the adjacent domain, which drive further polymerization. Thus, the biogenesis of large and topologically challenging IgM complexes is dictated by a local conformational switch in a peptide extension.