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Voelkl, K., Schulz-Trieglaff, E.K., Klein, R., and Dudanova, I.
(IMPRS-LS students in bold)
Front Neurosci, 2022, 16, 1022251.
doi: 10.3389/fnins.2022.1022251

Distinct histological alterations of cortical interneuron types in mouse models of Huntington's disease

Huntington's disease (HD) is a debilitating hereditary motor disorder caused by an expansion of the CAG triplet repeat in the Huntingtin gene. HD causes neurodegeneration particularly in the basal ganglia and neocortex. In the cortex, glutamatergic pyramidal neurons are known to be severely affected by the disease, but the involvement of GABAergic interneurons remains unclear. Here, we use a combination of immunostaining and genetic tracing to investigate histological changes in three major cortical interneuron types - parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP) interneurons - in the R6/2 and zQ175DN mouse models of HD. In R6/2 mice, we find a selective reduction in SST and VIP, but not PV-positive cells. However, genetic labeling reveals unchanged cell numbers for all the interneuron types, pointing to molecular marker loss in the absence of cell death. We also observe a reduction in cell body size for all three interneuron populations. Furthermore, we demonstrate progressive accumulation of mutant Huntingtin (mHTT) inclusion bodies in interneurons, which occurs faster in SST and VIP compared to PV cells. In contrast to the R6/2 model, heterozygous zQ175DN knock-in HD mice do not show any significant histological changes in cortical cell types at the age of 12 months, apart from the presence of mHTT inclusions, which are abundant in pyramidal neurons and rare in interneurons. Taken together, our findings point to differential molecular changes in cortical interneuron types of HD mice.



graduationCongratulations on your PhD!

Lorenzo Galanti

Role of DDK kinase in DNA double-strand break repair and insights into the DDK-Cdc5/PLK1 kinase complex

RG: Boris Pfander



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Sethi, A., Wei, H., Mishra, N., Segos, I., Lambie, E.J., Zanin, E., and Conradt, B.
PLoS Biol, 2022, 20, e3001786.
doi: 10.1371/journal.pbio.3001786

 A caspase-RhoGEF axis contributes to the cell size threshold for apoptotic death in developing Caenorhabditis elegans

A cell's size affects the likelihood that it will die. But how is cell size controlled in this context and how does cell size impact commitment to the cell death fate? We present evidence that the caspase CED-3 interacts with the RhoGEF ECT-2 in Caenorhabditis elegans neuroblasts that generate "unwanted" cells. We propose that this interaction promotes polar actomyosin contractility, which leads to unequal neuroblast division and the generation of a daughter cell that is below the critical "lethal" size threshold. Furthermore, we find that hyperactivation of ECT-2 RhoGEF reduces the sizes of unwanted cells. Importantly, this suppresses the "cell death abnormal" phenotype caused by the partial loss of ced-3 caspase and therefore increases the likelihood that unwanted cells die. A putative null mutation of ced-3 caspase, however, is not suppressed, which indicates that cell size affects CED-3 caspase activation and/or activity. Therefore, we have uncovered novel sequential and reciprocal interactions between the apoptosis pathway and cell size that impact a cell's commitment to the cell death fate.



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Güner, G., Aßfalg, M., Zhao, K., Dreyer, T., Lahiri, S., Lo, Y., Slivinschi, B.I., Imhof, A., Jocher, G., Strohm, L., Behrends, C., Langosch, D., Bronger, H., Nimsky, C., Bartsch, J.W., Riddell, S.R., Steiner, H., and Lichtenthaler, S.F.
(IMPRS-LS students are in bold)
EMBO Mol Med, 2022, e16084.
doi: 10.15252/emmm.202216084

Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ-secretase activity

Fn14 is a cell surface receptor with key functions in tissue homeostasis and injury but is also linked to chronic diseases. Despite its physiological and medical importance, the regulation of Fn14 signaling and turnover is only partly understood. Here, we demonstrate that Fn14 is cleaved within its transmembrane domain by the protease γ-secretase, resulting in secretion of the soluble Fn14 ectodomain (sFn14). Inhibition of γ-secretase in tumor cells reduced sFn14 secretion, increased full-length Fn14 at the cell surface, and enhanced TWEAK ligand-stimulated Fn14 signaling through the NFκB pathway, which led to enhanced release of the cytokine tumor necrosis factor. γ-Secretase-dependent sFn14 release was also detected ex vivo in primary tumor cells from glioblastoma patients, in mouse and human plasma and was strongly reduced in blood from human cancer patients dosed with a γ-secretase inhibitor prior to chimeric antigen receptor (CAR)-T-cell treatment. Taken together, our study demonstrates a novel function for γ-secretase in attenuating TWEAK/Fn14 signaling and suggests the use of sFn14 as an easily measurable pharmacodynamic biomarker to monitor γ-secretase activity in vivo.



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Huisjes, N.M.#, Retzer, T.M.#, Scherr, M.J., Agarwal, R., Rajappa, L., Safaric, B., Minnen, A., and Duderstadt, K.E.
(IMPRS-LS students are in bold, #equal contribution)
Elife, 2022, 11.
doi: 10.7554/elife.75899

Mars, a molecule archive suite for reproducible analysis and reporting of single-molecule properties from bioimages

The rapid development of new imaging approaches is generating larger and more complex datasets, revealing the time evolution of individual cells and biomolecules. Single-molecule techniques, in particular, provide access to rare intermediates in complex, multistage molecular pathways. However, few standards exist for processing these information-rich datasets, posing challenges for wider dissemination. Here, we present Mars, an open-source platform for storing and processing image-derived properties of biomolecules. Mars provides Fiji/ImageJ2 commands written in Java for common single-molecule analysis tasks using a Molecule Archive architecture that is easily adapted to complex, multistep analysis workflows. Three diverse workflows involving molecule tracking, multichannel fluorescence imaging, and force spectroscopy, demonstrate the range of analysis applications. A comprehensive graphical user interface written in JavaFX enhances biomolecule feature exploration by providing charting, tagging, region highlighting, scriptable dashboards, and interactive image views. The interoperability of ImageJ2 ensures Molecule Archives can easily be opened in multiple environments, including those written in Python using PyImageJ, for interactive scripting and visualization. Mars provides a flexible solution for reproducible analysis of image-derived properties, facilitating the discovery and quantitative classification of new biological phenomena with an open data format accessible to everyone.



graduationCongratulations on your PhD!

Kerstin Völkl

Hepatoma-derived growth factor is neuroprotective in models of Huntington’s disease

RG: Rüdiger Klein / Irina Dudanova



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Martín Caballero, L., Capella, M., Barrales, R.R., Dobrev, N., van Emden, T., Hirano, Y., Suma Sreechakram, V.N., Fischer-Burkart, S., Kinugasa, Y., Nevers, A., Rougemaille, M., Sinning, I., Fischer, T., Hiraoka, Y., and Braun, S.
(IMPRS-LS students are in bold)
Nat Struct Mol Biol, 2022, 29, 910-921.
doi: 10.1038/s41594-022-00831-6

The inner nuclear membrane protein Lem2 coordinates RNA degradation at the nuclear periphery

Transcriptionally silent chromatin often localizes to the nuclear periphery. However, whether the nuclear envelope (NE) is a site for post-transcriptional gene repression is not well understood. Here we demonstrate that Schizosaccharomyces pombe Lem2, an NE protein, regulates nuclear-exosome-mediated RNA degradation. Lem2 deletion causes accumulation of RNA precursors and meiotic transcripts and de-localization of an engineered exosome substrate from the nuclear periphery. Lem2 does not directly bind RNA but instead interacts with the exosome-targeting MTREC complex and its human homolog PAXT to promote RNA recruitment. This pathway acts largely independently of nuclear bodies where exosome factors assemble. Nutrient availability modulates Lem2 regulation of meiotic transcripts, implying that this pathway is environmentally responsive. Our work reveals that multiple spatially distinct degradation pathways exist. Among these, Lem2 coordinates RNA surveillance of meiotic transcripts and non-coding RNAs by recruiting exosome co-factors to the nuclear periphery.



Düsseldorf. On September 16th 2022, Petra Schwille, Director of the Department "Cellular and Molecular Biophysics" at the Max Planck Institute (MPI) of Biochemistry in Martinsried, will receive the Otto Warburg Medal 2021. The award ceremony will take place during the fall conference of the German Society for Biochemistry and Molecular Biology (GBM). The Otto Warburg Medal 2021 honors Petra Schwille's outstanding research work, which is also of great international interest. "I am very pleased about the recognition of my research and the attention that our approach to synthetic biology is thereby receiving. Investigating the elementary principles of cellular life has always held a special fascination for me and has so far opened up many exciting insights for us. It is therefore a great honor for me to receive this medal," says Petra Schwille, expressing her gratitude for the award.

At the MPI of Biochemistry, Petra Schwille has made it her goal to understand the fundamental principles of life. In order to do so, she is investigating self-assembly processes of biomolecules that may have been crucial for the development of the first cells. Through her work, she aims to gain new insights into basic principles of evolution, and thus into the emergence of the complexity of biological life. Ultimately, the physico-chemical prerequisites for the formation of the phenomenon of life are to be uncovered. Petra Ullrich, Marketing Director Europe at Elsevier, co-sponsor of the Otto Warburg Medal, says: "I am immensely pleased to honor a scientist who helps us understand the fundamental features of life and who is also an inspiration and role model for many young researchers." 

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Blessing, C., Apelt, K., van den Heuvel, D., Gonzalez-Leal, C., Rother, M.B., van der Woude, M., González-Prieto, R., Yifrach, A., Parnas, A., Shah, R.G., Kuo, T.T., Boer, D.E.C., Cai, J., Kragten, A., Kim, H.S., Schärer, O.D., Vertegaal, A.C.O., Shah, G.M., Adar, S., Lans, H., van Attikum, H., Ladurner, A.G., and Luijsterburg, M.S.
(IMPRS-LS students are in bold)
Nat Commun, 2022, 13, 4762.
doi: 10.1038/s41467-022-31820-4

XPC-PARP complexes engage the chromatin remodeler ALC1 to catalyze global genome DNA damage repair

Cells employ global genome nucleotide excision repair (GGR) to eliminate a broad spectrum of DNA lesions, including those induced by UV light. The lesion-recognition factor XPC initiates repair of helix-destabilizing DNA lesions, but binds poorly to lesions such as CPDs that do not destabilize DNA. How difficult-to-repair lesions are detected in chromatin is unknown. Here, we identify the poly-(ADP-ribose) polymerases PARP1 and PARP2 as constitutive interactors of XPC. Their interaction results in the XPC-stimulated synthesis of poly-(ADP-ribose) (PAR) by PARP1 at UV lesions, which in turn enables the recruitment and activation of the PAR-regulated chromatin remodeler ALC1. PARP2, on the other hand, modulates the retention of ALC1 at DNA damage sites. Notably, ALC1 mediates chromatin expansion at UV-induced DNA lesions, leading to the timely clearing of CPD lesions. Thus, we reveal how chromatin containing difficult-to-repair DNA lesions is primed for repair, providing insight into mechanisms of chromatin plasticity during GGR.



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Behrens, A., and Nedialkova, D.D.
STAR Protoc, 2022, 3, 101579.
doi: 10.1016/j.xpro.2022.101579

Experimental and computational workflow for the analysis of tRNA pools from eukaryotic cells by mim-tRNAseq

Quantifying tRNAs is crucial for understanding how they regulate mRNA translation but is hampered by their extensive sequence similarity and premature termination of reverse transcription at multiple modified nucleotides. Here, we describe the use of modification-induced misincorporation tRNA sequencing (mim-tRNAseq), which overcomes these limitations with optimized library construction and a comprehensive toolkit for data analysis and visualization. We outline algorithm improvements that enhance the efficiency and accuracy of read alignment and provide details on data analysis outputs using example datasets. For complete details on the use and execution of this protocol, please refer to Behrens et al. (2021).