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91 Publications visible to you, out of a total of 91
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

Lysosomal damage sensing and lysophagy initiation by SPG20-ITCH.

Abstract (Expand)

Cells respond to lysosomal membrane permeabilization by membrane repair or selective macroautophagy of damaged lysosomes, termed lysophagy, but it is not fully understood how this decision is made. … Here, we uncover a pathway in human cells that detects lipid bilayer perturbations in the limiting membrane of compromised lysosomes, which fail to be repaired, and then initiates ubiquitin-triggered lysophagy. We find that SPG20 binds the repair factor IST1 on damaged lysosomes and, importantly, integrates that with the detection of damage-associated lipid-packing defects of the lysosomal membrane. Detection occurs via sensory amphipathic helices in SPG20 before rupture of the membrane. If lipid-packing defects are extensive, such as during lipid peroxidation, SPG20 recruits and activates ITCH, which marks the damaged lysosome with lysine-63-linked ubiquitin chains to initiate lysophagy and thus triages the lysosome for destruction. With SPG20 being linked to neurodegeneration, these findings highlight the relevance of a coordinated lysosomal damage response for cellular homeostasis.

Authors: Pinki Gahlot, Bojana Kravic, Giulia Rota, Johannes van den Boom, Sophie Levantovsky, Nina Schulze, Elena Maspero, Simona Polo, Christian Behrends, Hemmo Meyer

Date Published: 18th 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

Injury-specific factors in the cerebrospinal fluid regulate astrocyte plasticity in the human brain.

Abstract (Expand)

The glial environment influences neurological disease progression, yet much of our knowledge still relies on preclinical animal studies, especially regarding astrocyte heterogeneity. In murine models … of traumatic brain injury, beneficial functions of proliferating reactive astrocytes on disease outcome have been unraveled, but little is known regarding if and when they are present in human brain pathology. Here we examined a broad spectrum of pathologies with and without intracerebral hemorrhage and found a striking correlation between lesions involving blood-brain barrier rupture and astrocyte proliferation that was further corroborated in an assay probing for neural stem cell potential. Most importantly, proteomic analysis unraveled a crucial signaling pathway regulating this astrocyte plasticity with GALECTIN3 as a novel marker for proliferating astrocytes and the GALECTIN3-binding protein LGALS3BP as a functional hub mediating astrocyte proliferation and neurosphere formation. Taken together, this work identifies a therapeutically relevant astrocyte response and their molecular regulators in different pathologies affecting the human cerebral cortex.

Authors: Swetlana Sirko, Christian Schichor, Patrizia Della Vecchia, Fabian Metzger, Giovanna Sonsalla, Tatiana Simon, Martina Bürkle, Sofia Kalpazidou, Jovica Ninkovic, Giacomo Masserdotti, Jean-Frederic Sauniere, Valentina Iacobelli, Stefano Iacobelli, Claire Delbridge, Stefanie M Hauck, Jörg-Christian Tonn, Magdalena Götz

Date Published: 8th Dec 2023

Publication Type: Journal

High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via κ-opioid signaling.

Abstract (Expand)

Oxytocin-expressing paraventricular hypothalamic neurons (PVN<sup>OT</sup> neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy … homeostasis. However, the molecular underpinnings by which PVN<sup>OT</sup> neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVN<sup>OT</sup> neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on a chow diet. Notably, exposing wild-type mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity toward CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVN<sup>OT</sup> neurons. Restoring OT pathways in diet-induced obese (DIO) mice via chemogenetics or polypharmacology sufficiently re-establishes CCK's anorexigenic effects. Last, by single-cell profiling, we identify a specialized PVN<sup>OT</sup> neuronal subpopulation with increased κ-opioid signaling under an HFHS diet, which restrains their CCK-evoked activation. In sum, we document a (patho)mechanism by which PVN<sup>OT</sup> signaling uncouples a gut-brain satiation pathway under obesogenic conditions.

Authors: Tim Gruber, Franziska Lechner, Cahuê Murat, Raian E Contreras, Eva Sanchez-Quant, Viktorian Miok, Konstantinos Makris, Ophélia Le Thuc, Ismael González-García, Elena García-Clave, Ferdinand Althammer, Quirin Krabichler, Lisa M DeCamp, Russell G Jones, Dominik Lutter, Rhiannan H Williams, Paul T Pfluger, Timo D Müller, Stephen C Woods, John Andrew Pospisilik, Celia P Martinez-Jimenez, Matthias H Tschöp, Valery Grinevich, Cristina Garcia-Caceres

Date Published: 31st Oct 2023

Publication Type: Journal

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