Regulation der Wirkung von Antidepressiva durch Sphingomyelin- und Ceramid-kontrollierte Autophagie
Anatomie und Physiologie
Zusammenfassung der Projektergebnisse
In the present grant period we were able to identify a novel mechanism how major depressive disorder is induced. We demonstrated that major depressive disorder in humans, chronic unpredictable stress or glucocorticoid-mediated stress in mice results in an increase of ceramide in the blood plasma. Neutralization of ceramide in the blood plasma prevented or cured, respectively, major depressive disorder in mice. The increase of ceramide is mediated by neutral sphingomyelinase 2 (Smpd3). This is a completely novel mechanism to explain major depressive disorder. We identified targets of blood plasma ceramide in endothelial cells of the brain, i.e. phospholipase D and its product phosphatidic acid. Ceramide inhibits the function of phospholipase D and reduces phosphatidic acid. Since phosphatidic acid is much more polar than ceramide, it is able to diffuse into the brain and regulate functions in neurons and glia cells. We identified TrkB, induction of tyrosine-nitrosylation and most importantly the regulation of autophagy as targets of phosphatidic acid. We further confirmed the acid sphingomyelinase as target of antidepressants and applied this finding to the infection of cells and patients receiving antidepressants with SARS-CoV-2.
Projektbezogene Publikationen (Auswahl)
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Anxiety and Depression Are Related to Higher Activity of Sphingolipid Metabolizing Enzymes in the Rat Brain. Cells, 9(5), 1239.
Zoicas, Iulia; Mühle, Christiane; Schmidtner, Anna K.; Gulbins, Erich; Neumann, Inga D. & Kornhuber, Johannes
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Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells. Cell Reports Medicine, 1(8), 100142.
Carpinteiro, Alexander; Edwards, Michael J.; Hoffmann, Markus; Kochs, Georg; Gripp, Barbara; Weigang, Sebastian; Adams, Constantin; Carpinteiro, Elisa; Gulbins, Anne; Keitsch, Simone; Sehl, Carolin; Soddemann, Matthias; Wilker, Barbara; Kamler, Markus; Bertsch, Thomas; Lang, Karl S.; Patel, Sameer; Wilson, Gregory C.; Walter, Silke ... & Gulbins, Erich
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Comorbid medical conditions are a key factor to understand the relationship between psychiatric disorders and COVID-19-related mortality: Results from 49,089 COVID-19 inpatients. Molecular Psychiatry, 27(3), 1278-1280.
Hoertel, Nicolas; Sánchez-Rico, Marina; Herrera-Morueco, Juan José; de la Muela, Pedro; Gulbins, Erich; Kornhuber, Johannes; Carpinteiro, Alexander; Becker, Katrin Anne; Cougoule, Céline & Limosin, Frédéric
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mRNA Expression of SMPD1 Encoding Acid Sphingomyelinase Decreases upon Antidepressant Treatment. International Journal of Molecular Sciences, 22(11), 5700.
Rhein, Cosima; Zoicas, Iulia; Marx, Lena M.; Zeitler, Stefanie; Hepp, Tobias; von Zimmermann; Claudia; Mühle, Christiane; Richter-Schmidinger, Tanja; Lenz, Bernd; Erim, Yesim; Reichel, Martin; Gulbins, Erich & Kornhuber, Johannes
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Repurposing antidepressants inhibiting the sphingomyelinase acid/ceramide system against COVID-19: current evidence and potential mechanisms. Molecular Psychiatry, 26(12), 7098-7099.
Hoertel, Nicolas; Sánchez-Rico, Marina; Cougoule, Céline; Gulbins, Erich; Kornhuber, Johannes; Carpinteiro, Alexander; Becker, Katrin Anne; Reiersen, Angela M.; Lenze, Eric J.; Seftel, David; Lemogne, Cédric & Limosin, Frédéric
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Ceramide levels in blood plasma correlate with major depressive disorder severity and its neutralization abrogates depressive behavior in mice. Journal of Biological Chemistry, 298(8), 102185.
Soddemann, Matthias; Keitsch, Simone; Scherbaum, Norbert; Müller, Bernhard W.; Lang, Undine E.; Linnemann, Christoph; Kleuser, Burkhard; Müller, Christian P.; Kornhuber, Johannes & Gulbins, Erich
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Molecular targets of endothelial phosphatidic acid regulating major depressive disorder. Journal of Neurochemistry, 163(4), 357-369.
Edwards, Michael J.; Wilson, Gregory C.; Keitsch, Simone; Soddemann, Matthias; Wilker, Barbara; Müller, Christian P.; Kornhuber, Johannes & Gulbins, Erich
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Stress induces major depressive disorder by a neutral sphingomyelinase 2-mediated accumulation of ceramide-enriched exosomes in the blood plasma. Journal of Molecular Medicine, 100(10), 1493-1508.
Schumacher, Fabian; Carpinteiro, Alexander; Edwards, Michael J.; Wilson, Gregory C.; Keitsch, Simone; Soddemann, Matthias; Wilker, Barbara; Kleuser, Burkhard; Becker, Katrin Anne; Müller, Christian P.; Kornhuber, Johannes & Gulbins, Erich
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Development of Comorbid Depression after Social Fear Conditioning in Mice and Its Effects on Brain Sphingolipid Metabolism. Cells, 12(10), 1355.
Zoicas, Iulia; Mühle, Christiane; Schumacher, Fabian; Kleuser, Burkhard & Kornhuber, Johannes
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Role of Tyrosine Nitrosylation in Stress-Induced Major Depressive Disorder: Mechanisms and Implications. International Journal of Molecular Sciences, 24(19), 14626.
Wilson, Gregory C.; Keitsch, Simone; Soddemann, Matthias; Wilker, Barbara; Edwards, Michael J. & Gulbins, Erich
