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93 Publications visible to you, out of a total of 93
A ubiquitin-specific, proximity-based labeling approach for the identification of ubiquitin ligase substrates.

Abstract (Expand)

Over 600 E3 ligases in humans execute ubiquitination of specific target proteins in a spatiotemporal manner to elicit desired signaling effects. Here, we developed a ubiquitin-specific proximity-based … labeling method to selectively biotinylate substrates of a given ubiquitin ligase. By fusing the biotin ligase BirA and an Avi-tag variant to the candidate E3 ligase and ubiquitin, respectively, we were able to specifically enrich bona fide substrates of a ligase using a one-step streptavidin pulldown under denaturing conditions. We applied our method, which we named Ub-POD, to the really interesting new gene (RING) E3 ligase RAD18 and identified proliferating cell nuclear antigen and several other critical players in the DNA damage repair pathway. Furthermore, we successfully applied Ub-POD to the RING ubiquitin ligase tumor necrosis factor receptor-associated factor 6 and a U-box-type E3 ubiquitin ligase carboxyl terminus of Hsc70-interacting protein. We anticipate that our method could be widely adapted to all classes of ubiquitin ligases to identify substrates.

Authors: Urbi Mukhopadhyay, Sophie Levantovsky, Teresa Maria Carusone, Sarah Gharbi, Frank Stein, Christian Behrends, Sagar Bhogaraju

Date Published: 9th Aug 2024

Publication Type: Journal

Innate immune memory after brain injury drives inflammatory cardiac dysfunction.

Abstract (Expand)

The medical burden of stroke extends beyond the brain injury itself and is largely determined by chronic comorbidities that develop secondarily. We hypothesized that these comorbidities might share a … common immunological cause, yet chronic effects post-stroke on systemic immunity are underexplored. Here, we identify myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Single-cell sequencing revealed persistent pro-inflammatory changes in monocytes/macrophages in multiple organs up to 3 months after brain injury, notably in the heart, leading to cardiac fibrosis and dysfunction in both mice and stroke patients. IL-1β was identified as a key driver of epigenetic changes in innate immune memory. These changes could be transplanted to naive mice, inducing cardiac dysfunction. By neutralizing post-stroke IL-1β or blocking pro-inflammatory monocyte trafficking with a CCR2/5 inhibitor, we prevented post-stroke cardiac dysfunction. Such immune-targeted therapies could potentially prevent various IL-1β-mediated comorbidities, offering a framework for secondary prevention immunotherapy.

Authors: Alba Simats, Sijia Zhang, Denise Messerer, Faye Chong, Sude Beşkardeş, Aparna Sharma Chivukula, Jiayu Cao, Simon Besson-Girard, Felipe A Montellano, Caroline Morbach, Olga Carofiglio, Alessio Ricci, Stefan Roth, Gemma Llovera, Rashween Singh, Yiming Chen, Severin Filser, Nikolaus Plesnila, Christian Braun, Hannah Spitzer, Özgün Gökçe, Martin Dichgans, Peter U Heuschmann, Kinta Hatakeyama, Eduardo Beltrán, Sebastian Clauss, Boyan Bonev, Christian Schulz, Arthur Liesz

Date Published: 22nd Jul 2024

Publication Type: Journal

Rational correction of pathogenic conformational defects in HTRA1.

Abstract (Expand)

Loss-of-function mutations in the homotrimeric serine protease HTRA1 cause cerebral vasculopathy. Here, we establish independent approaches to achieve the functional correction of trimer assembly … defects. Focusing on the prototypical R274Q mutation, we identify an HTRA1 variant that promotes trimer formation thus restoring enzymatic activity in vitro. Genetic experiments in Htra1<sup>R274Q</sup> mice further demonstrate that expression of this protein-based corrector in trans is sufficient to stabilize HtrA1-R274Q and restore the proteomic signature of the brain vasculature. An alternative approach employs supramolecular chemical ligands that shift the monomer-trimer equilibrium towards proteolytically active trimers. Moreover, we identify a peptidic ligand that activates HTRA1 monomers. Our findings open perspectives for tailored protein repair strategies.

Authors: Nathalie Beaufort, Linda Ingendahl, Melisa Merdanovic, Andree Schmidt, David Podlesainski, Tim Richter, Thorben Neumann, Michael Kuszner, Ingrid R Vetter, Patricia Stege, Steven G Burston, Anto Filipovic, Yasser B Ruiz-Blanco, Kenny Bravo-Rodriguez, Joel Mieres-Perez, Christine Beuck, Stephan Uebel, Monika Zobawa, Jasmin Schillinger, Rainer Malik, Katalin Todorov-Völgyi, Juliana Rey, Annabell Roberti, Birte Hagemeier, Benedikt Wefers, Stephan A Müller, Wolfgang Wurst, Elsa Sanchez-Garcia, Alexander Zimmermann, Xiao-Yu Hu, Tim Clausen, Robert Huber, Stefan F Lichtenthaler, Carsten Schmuck, Michael Giese, Markus Kaiser, Michael Ehrmann, Martin Dichgans

Date Published: 16th Jul 2024

Publication Type: Journal

Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target.

Abstract (Expand)

Amyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease and lacks effective disease-modifying treatments. This study utilizes a comprehensive multiomic approach to investigate the … early and sex-specific molecular mechanisms underlying ALS. By analyzing the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, alongside four transgenic mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS), we have uncovered significant molecular alterations associated with the disease. Here, we show that males exhibit more pronounced changes in molecular pathways compared to females. Our integrated analysis of transcriptomes, (phospho)proteomes, and miRNAomes also identified distinct ALS subclusters in humans, characterized by variations in immune response, extracellular matrix composition, mitochondrial function, and RNA processing. The molecular signatures of human subclusters were reflected in specific mouse models. Our study highlighted the mitogen-activated protein kinase (MAPK) pathway as an early disease mechanism. We further demonstrate that trametinib, a MAPK inhibitor, has potential therapeutic benefits in vitro and in vivo, particularly in females, suggesting a direction for developing targeted ALS treatments.

Authors: Lucas Caldi Gomes, Sonja Hänzelmann, Fabian Hausmann, Robin Khatri, Sergio Oller, Mojan Parvaz, Laura Tzeplaeff, Laura Pasetto, Marie Gebelin, Melanie Ebbing, Constantin Holzapfel, Stefano Fabrizio Columbro, Serena Scozzari, Johanna Knöferle, Isabell Cordts, Antonia F Demleitner, Marcus Deschauer, Claudia Dufke, Marc Sturm, Qihui Zhou, Pavol Zelina, Emma Sudria-Lopez, Tobias B Haack, Sebastian Streb, Magdalena Kuzma-Kozakiewicz, Dieter Edbauer, R Jeroen Pasterkamp, Endre Laczko, Hubert Rehrauer, Ralph Schlapbach, Christine Carapito, Valentina Bonetto, Stefan Bonn, Paul Lingor

Date Published: 1st Jul 2024

Publication Type: Journal

T cell-mediated microglial activation triggers myelin pathology in a mouse model of amyloidosis.

Abstract (Expand)

Age-related myelin damage induces inflammatory responses, yet its involvement in Alzheimer's disease remains uncertain, despite age being a major risk factor. Using a mouse model of Alzheimer's … disease, we found that amyloidosis itself triggers age-related oligodendrocyte and myelin damage. Mechanistically, CD8<sup>+</sup> T cells promote the progressive accumulation of abnormally interferon-activated microglia that display myelin-damaging activity. Thus, our data suggest that immune responses against myelinating oligodendrocytes may contribute to neurodegenerative diseases with amyloidosis.

Authors: Shreeya Kedia, Hao Ji, Ruoqing Feng, Peter Androvic, Lena Spieth, Lu Liu, Jonas Franz, Hanna Zdiarstek, Katrin Perez Anderson, Cem Kaboglu, Qian Liu, Nicola Mattugini, Fatma Cherif, Danilo Prtvar, Ludovico Cantuti-Castelvetri, Arthur Liesz, Martina Schifferer, Christine Stadelmann, Sabina Tahirovic, Özgün Gökçe, Mikael Simons

Date Published: 27th Jun 2024

Publication Type: Journal

The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.

Abstract (Expand)

The beta-secretase BACE1 is a central drug target for Alzheimer's disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet, little is known about physiological … BACE2 substrates and functions in vivo. Here, we identify BACE2 as the protease shedding the lymphangiogenic vascular endothelial growth factor receptor 3 (VEGFR3). Inactivation of BACE2, but not BACE1, inhibited shedding of VEGFR3 from primary human lymphatic endothelial cells (LECs) and reduced release of the shed, soluble VEGFR3 (sVEGFR3) ectodomain into the blood of mice, non-human primates and humans. Functionally, BACE2 inactivation increased full-length VEGFR3 and enhanced VEGFR3 signaling in LECs and also in vivo in zebrafish, where enhanced migration of LECs was observed. Thus, this study identifies BACE2 as a modulator of lymphangiogenic VEGFR3 signaling and demonstrates the utility of sVEGFR3 as a pharmacodynamic plasma marker for BACE2 activity in vivo, a prerequisite for developing BACE1-selective inhibitors for a safer prevention of Alzheimer's disease.

Authors: A. Schmidt, B. Hrupka, F. van Bebber, S. Sunil Kumar, X. Feng, S. K. Tschirner, M. Assfalg, S. A. Muller, L. S. Hilger, L. I. Hofmann, M. Pigoni, G. Jocher, I. Voytyuk, E. L. Self, M. Ito, K. Hyakkoku, A. Yoshimura, N. Horiguchi, R. Feederle, B. De Strooper, S. Schulte-Merker, E. Lammert, D. Moechars, B. Schmid, S. F. Lichtenthaler

Date Published: 18th Jun 2024

Publication Type: Journal

Peripheral expression of brain-penetrant progranulin rescues pathologies in mouse models of frontotemporal lobar degeneration.

Abstract (Expand)

Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD-<i>GRN</i>). Multiple therapeutic … strategies are in clinical development to restore PGRN in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain-penetrant (b) PGRN variant [AAV(L):bPGRN] in two mouse models of FTLD-<i>GRN</i>, namely, <i>Grn</i> knockout and <i>GrnxTmem106b</i> double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs and maintains sustained concentrations of PGRN in the brain after a single dose. AAV(L):bPGRN treatment reduced several FTLD-<i>GRN</i>-associated pathologies including severe motor function deficits, aberrant TDP-43 phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis, and neurodegeneration in the brain. The potential translatability of our findings was tested in an in vitro model using cocultured human induced pluripotent stem cell (hiPSC)-derived microglia lacking PGRN and TMEM106B and wild-type hiPSC-derived neurons. As in mice, aberrant TDP-43, lysosomal dysfunction, and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies ameliorate FTLD-<i>GRN</i> relevant phenotypes including TDP-43 pathology, neurodegeneration, and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD-<i>GRN</i> and potentially other CNS disorders.

Authors: Marvin Reich, Matthew J Simon, Beate Polke, Iñaki Paris, Georg Werner, Christian Schrader, Lena Spieth, Sonnet S Davis, Sophie Robinson, Gabrielly Lunkes de Melo, Lennart Schlaphoff, Katrin Buschmann, Stefan Berghoff, Todd Logan, Brigitte Nuscher, Lis de Weerd, Dieter Edbauer, Mikael Simons, Jung H Suh, Thomas Sandmann, Mihalis S Kariolis, Sarah L DeVos, Joseph W Lewcock, Dominik Paquet, Anja Capell, Gilbert Di Paolo, Christian Haass

Date Published: 5th Jun 2024

Publication Type: Journal

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