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64 Publications visible to you, out of a total of 64
Genetically proxied HTRA1 protease activity and circulating levels independently predict risk of ischemic stroke and coronary artery disease.

Abstract (Expand)

Genetic variants in HTRA1 are associated with stroke risk. However, the mechanisms mediating this remain largely unknown, as does the full spectrum of phenotypes associated with genetic variation in … HTRA1. Here we show that rare HTRA1 variants are linked to ischemic stroke in the UK Biobank and BioBank Japan. Integrating data from biochemical experiments, we next show that variants causing loss of protease function associated with ischemic stroke, coronary artery disease and skeletal traits in the UK Biobank and MyCode cohorts. Moreover, a common variant modulating circulating HTRA1 mRNA and protein levels enhances the risk of ischemic stroke and coronary artery disease while lowering the risk of migraine and macular dystrophy in genome-wide association study, UK Biobank, MyCode and BioBank Japan data. We found no interaction between proxied HTRA1 activity and levels. Our findings demonstrate the role of HTRA1 for cardiovascular diseases and identify two mechanisms as potential targets for therapeutic interventions.

Authors: R. Malik, N. Beaufort, J. Li, K. Tanaka, M. K. Georgakis, Y. He, M. Koido, C. Terao, B. Japan, C. D. Anderson, Y. Kamatani, R. Zand, M. Dichgans

Date Published: 28th Aug 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

A TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice.

Abstract (Expand)

Heterozygous mutations in the TBK1 gene can cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The majority of TBK1-ALS/FTD patients carry deleterious loss-of-expression … mutations, and it is still unclear which TBK1 function leads to neurodegeneration. We investigated the impact of the pathogenic TBK1 missense variant p.E696K, which does not abolish protein expression, but leads to a selective loss of TBK1 binding to the autophagy adaptor protein and TBK1 substrate optineurin. Using organelle-specific proteomics, we found that in a knock-in mouse model and human iPSC-derived motor neurons, the p.E696K mutation causes presymptomatic onset of autophagolysosomal dysfunction in neurons precipitating the accumulation of damaged lysosomes. This is followed by a progressive, age-dependent motor neuron disease. Contrary to the phenotype of mice with full Tbk1 knock-out, RIPK/TNF-alpha-dependent hepatic, neuronal necroptosis, and overt autoinflammation were not detected. Our in vivo results indicate autophagolysosomal dysfunction as a trigger for neurodegeneration and a promising therapeutic target in TBK1-ALS/FTD.

Authors: D. Brenner, K. Sieverding, J. Srinidhi, S. Zellner, C. Secker, R. Yilmaz, J. Dyckow, S. Amr, A. Ponomarenko, E. Tunaboylu, Y. Douahem, J. S. Schlag, L. Rodriguez Martinez, G. Kislinger, C. Niemann, K. Nalbach, W. P. Ruf, J. Uhl, J. Hollenbeck, L. Schirmer, A. Catanese, C. S. Lobsiger, K. M. Danzer, D. Yilmazer-Hanke, C. Munch, P. Koch, A. Freischmidt, M. Fetting, C. Behrends, R. Parlato, J. H. Weishaupt

Date Published: 6th May 2024

Publication Type: Journal

Proteomics of mouse brain endothelium uncovers dysregulation of vesicular transport pathways during aging.

Abstract (Expand)

Age-related decline in brain endothelial cell (BEC) function contributes critically to neurological disease. Comprehensive atlases of the BEC transcriptome have become available, but results from … proteomic profiling are lacking. To gain insights into endothelial pathways affected by aging, we developed a magnetic-activated cell sorting-based mouse BEC enrichment protocol compatible with proteomics and resolved the profiles of protein abundance changes during aging. Unsupervised cluster analysis revealed a segregation of age-related protein dynamics with biological functions, including a downregulation of vesicle-mediated transport. We found a dysregulation of key regulators of endocytosis and receptor recycling (most prominently Arf6), macropinocytosis and lysosomal degradation. In gene deletion and overexpression experiments, Arf6 affected endocytosis pathways in endothelial cells. Our approach uncovered changes not picked up by transcriptomic studies, such as accumulation of vesicle cargo and receptor ligands, including Apoe. Proteomic analysis of BECs from Apoe-deficient mice revealed a signature of accelerated aging. Our findings provide a resource for analysing BEC function during aging.

Authors: K. Todorov-Volgyi, J. Gonzalez-Gallego, S. A. Muller, N. Beaufort, R. Malik, M. Schifferer, M. I. Todorov, D. Crusius, S. Robinson, A. Schmidt, J. Korbelin, F. Bareyre, A. Erturk, C. Haass, M. Simons, D. Paquet, S. F. Lichtenthaler, M. Dichgans

Date Published: 22nd Apr 2024

Publication Type: Journal

Direct neuronal reprogramming of NDUFS4 patient cells identifies the unfolded protein response as a novel general reprogramming hurdle.

Abstract (Expand)

Mitochondria account for essential cellular pathways, from ATP production to nucleotide metabolism, and their deficits lead to neurological disorders and contribute to the onset of age-related diseases. … Direct neuronal reprogramming aims at replacing neurons lost in such conditions, but very little is known about the impact of mitochondrial dysfunction on the direct reprogramming of human cells. Here, we explore the effects of mitochondrial dysfunction on the neuronal reprogramming of induced pluripotent stem cell (iPSC)-derived astrocytes carrying mutations in the NDUFS4 gene, important for Complex I and associated with Leigh syndrome. This led to the identification of the unfolded protein response as a major hurdle in the direct neuronal conversion of not only astrocytes and fibroblasts from patients but also control human astrocytes and fibroblasts. Its transient inhibition potently improves reprogramming by influencing the mitochondria-endoplasmic-reticulum-stress-mediated pathways. Taken together, disease modeling using patient cells unraveled novel general hurdles and ways to overcome these in human astrocyte-to-neuron reprogramming.

Authors: G. Sonsalla, A. B. Malpartida, T. Riedemann, M. Gusic, E. Rusha, G. Bulli, S. Najas, A. Janjic, B. A. Hersbach, P. Smialowski, M. Drukker, W. Enard, J. H. M. Prehn, H. Prokisch, M. Gotz, G. Masserdotti

Date Published: 3rd Apr 2024

Publication Type: Journal

Shared inflammatory glial cell signature after stab wound injury, revealed by spatial, temporal, and cell-type-specific profiling of the murine cerebral cortex.

Abstract (Expand)

Traumatic brain injury leads to a highly orchestrated immune- and glial cell response partially responsible for long-lasting disability and the development of secondary neurodegenerative diseases. A … holistic understanding of the mechanisms controlling the responses of specific cell types and their crosstalk is required to develop an efficient strategy for better regeneration. Here, we combine spatial and single-cell transcriptomics to chart the transcriptomic signature of the injured male murine cerebral cortex, and identify specific states of different glial cells contributing to this signature. Interestingly, distinct glial cells share a large fraction of injury-regulated genes, including inflammatory programs downstream of the innate immune-associated pathways Cxcr3 and Tlr1/2. Systemic manipulation of these pathways decreases the reactivity state of glial cells associated with poor regeneration. The functional relevance of the discovered shared signature of glial cells highlights the importance of our resource enabling comprehensive analysis of early events after brain injury.

Authors: Christina Koupourtidou, Veronika Schwarz, Hananeh Aliee, Simon Frerich, Judith Fischer-Sternjak, Riccardo Bocchi, Tatiana Simon-Ebert, Xianshu Bai, Swetlana Sirko, Frank Kirchhoff, Martin Dichgans, Magdalena Götz, Fabian J Theis, Jovica Ninkovic

Date Published: 3rd Apr 2024

Publication Type: Journal

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