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Published year: 202313
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

Microglia-mediated demyelination protects against CD8(+) T cell-driven axon degeneration in mice carrying PLP defects.

Abstract (Expand)

Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic … neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8(+) T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.

Authors: J. Groh, T. Abdelwahab, Y. Kattimani, M. Horner, S. Loserth, V. Gudi, R. Adalbert, F. Imdahl, A. E. Saliba, M. Coleman, M. Stangel, M. Simons, R. Martini

Date Published: 30th Oct 2023

Publication Type: Journal

Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution.

Abstract (Expand)

Various cellular sources hamper interpretation of positron emission tomography (PET) biomarkers in the tumor microenvironment (TME). We developed an approach of immunomagnetic cell sorting after in … vivo radiotracer injection (scRadiotracing) with three-dimensional (3D) histology to dissect the cellular allocation of PET signals in the TME. In mice with implanted glioblastoma, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs), validated by protein levels. Translation of in vitro scRadiotracing to patients with glioma immediately after tumor resection confirmed higher single-cell TSPO tracer uptake of tumor cells compared to immune cells. Across species, cellular radiotracer uptake explained the heterogeneity of individual TSPO-PET signals. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma; however, proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D histology facilitates precise allocation of PET signals and serves to validate emerging novel TAM-specific radioligands.

Authors: L. M. Bartos, S. V. Kirchleitner, Z. I. Kolabas, S. Quach, A. Beck, J. Lorenz, J. Blobner, S. A. Mueller, S. Ulukaya, L. Hoeher, I. Horvath, K. Wind-Mark, A. Holzgreve, V. C. Ruf, L. Gold, L. H. Kunze, S. T. Kunte, P. Beumers, H. E. Park, M. Antons, A. Zatcepin, N. Briel, L. Hoermann, R. Schaefer, D. Messerer, P. Bartenstein, M. J. Riemenschneider, S. Lindner, S. Ziegler, J. Herms, S. F. Lichtenthaler, A. Erturk, J. C. Tonn, L. von Baumgarten, N. L. Albert, M. Brendel

Date Published: 27th Oct 2023

Publication Type: Journal

A genome-wide in vivo CRISPR screen identifies essential regulators of T cell migration to the CNS in a multiple sclerosis model.

Abstract (Expand)

Multiple sclerosis (MS) involves the infiltration of autoreactive T cells into the CNS, yet we lack a comprehensive understanding of the signaling pathways that regulate this process. Here, we conducted … a genome-wide in vivo CRISPR screen in a rat MS model and identified 5 essential brakes and 18 essential facilitators of T cell migration to the CNS. While the transcription factor ETS1 limits entry to the CNS by controlling T cell responsiveness, three functional modules, centered around the adhesion molecule alpha4-integrin, the chemokine receptor CXCR3 and the GRK2 kinase, are required for CNS migration of autoreactive CD4(+) T cells. Single-cell analysis of T cells from individuals with MS confirmed that the expression of these essential regulators correlates with the propensity of CD4(+) T cells to reach the CNS. Our data thus reveal key regulators of the fundamental step in the induction of MS lesions.

Authors: A. Kendirli, C. de la Rosa, K. F. Lammle, K. Eglseer, I. J. Bauer, V. Kavaka, S. Winklmeier, L. Zhuo, C. Wichmann, L. A. Gerdes, T. Kumpfel, K. Dornmair, E. Beltran, M. Kerschensteiner, N. Kawakami

Date Published: 4th Oct 2023

Publication Type: Journal

Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions.

Abstract (Expand)

Inflammation in the central nervous system can impair the function of neuronal mitochondria and contributes to axon degeneration in the common neuroinflammatory disease multiple sclerosis (MS). Here … we combine cell-type-specific mitochondrial proteomics with in vivo biosensor imaging to dissect how inflammation alters the molecular composition and functional capacity of neuronal mitochondria. We show that neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP deficiency, which precedes mitochondrial oxidation and calcium overload. This axonal energy deficiency is associated with impaired electron transport chain function, but also an upstream imbalance of tricarboxylic acid (TCA) cycle enzymes, with several, including key rate-limiting, enzymes being depleted in neuronal mitochondria in experimental models and in MS lesions. Notably, viral overexpression of individual TCA enzymes can ameliorate the axonal energy deficits in neuroinflammatory lesions, suggesting that TCA cycle dysfunction in MS may be amendable to therapy.

Authors: Y. H. Tai, D. Engels, G. Locatelli, I. Emmanouilidis, C. Fecher, D. Theodorou, S. A. Muller, S. Licht-Mayer, M. Kreutzfeldt, I. Wagner, N. P. de Mello, S. N. Gkotzamani, L. Trovo, A. Kendirli, A. Aljovic, M. O. Breckwoldt, R. Naumann, F. M. Bareyre, F. Perocchi, D. Mahad, D. Merkler, S. F. Lichtenthaler, M. Kerschensteiner, T. Misgeld

Date Published: 25th Aug 2023

Publication Type: Journal

The COP9 signalosome reduces neuroinflammation and attenuates ischemic neuronal stress in organotypic brain slice culture model.

Abstract (Expand)

The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is a deNEDDylase controlling ubiquitination activity of cullin-RING-E3 ligases (CRLs) and thus the levels of key cellular proteins. While … the CSN and its catalytic subunit CSN5 have been extensively studied in cancer, its role in inflammatory and neurological diseases is less understood. Following verification that CSN5 is expressed in mouse and human brain, here we studied the role of the CSN in neuroinflammation and ischemic neuronal damage employing models of relevant brain-resident cell types, an ex vivo organotypic brain slice culture model, and the CRL NEDDylation state-modifying drugs MLN4924 and CSN5i-3, which mimic and inhibit, respectively, CSN5 deNEDDylase activity. Untargeted mass spectrometry-based proteomics revealed that MLN4924 and CSN5i-3 substantially alter the microglial proteome, including inflammation-related proteins. Applying these drugs and mimicking microglial and endothelial inflammation as well as ischemic neuronal stress by TNF and oxygen-glucose-deprivation/reoxygenation (OGD/RO) treatment, respectively, we could link CSN5/CSN-mediated cullin deNEDDylation to reduction of microglial inflammation, attenuated cerebral endothelial inflammation, improved barrier integrity, as well as protection from ischemic stress-induced neuronal cell death. Specifically, MLN4924 reduced phagocytic activity, motility, and inflammatory cytokine expression of microglial cells, and this was linked to inhibition of inflammation-induced NF-kappaB and Akt signaling. Inversely, Csn5 knockdown and CSN5i-3 increased NF-kappaB signaling. Moreover, MLN4924 abrogated TNF-induced NF-kappaB signaling in cerebral microvascular endothelial cells (hCMECs) and rescued hCMEC monolayers from OGD/RO-triggered barrier leakage, while CSN5i-3 exacerbated permeability. In an ex vivo organotypic brain slice model of ischemia/reperfusion stress, MLN4924 protected from neuronal death, while CSN5i-3 impaired neuronal survival. Neuronal damage was attributable to microglial activation and inflammatory cytokines, as indicated by microglial shape tracking and TNF-blocking experiments. Our results indicate a protective role of the CSN in neuroinflammation via brain-resident cell types involved in ischemic brain disease and implicate CSN activity-mimicking deNEDDylating drugs as potential therapeutics.

Authors: Y. Tian, J. Milic, L. S. Monasor, R. Chakraborty, S. Wang, Y. Yuan, Y. Asare, C. Behrends, S. Tahirovic, J. Bernhagen

Date Published: 19th Aug 2023

Publication Type: Journal

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