Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects

Kalinichenko L, Mühle C, Jia T, Anderheiden F, Datz M, Eberle AL, Eulenburg V, Granzow J, Hofer MJ, Hohenschild J, Huber S, Kämpf S, Kogias G, Lacatusu L, Lugmair C, Taku SM, Meixner D, Tesch N, Praetner M, Rhein C, Sauer C, Scholz J, Ulrich F, Valenta F, Weigand E, Werner M, Tay N, Mc Veigh CJ, Haase J, Wang AL, Abdel-Hafiz L, Huston JP, Smaga I, Frankowska M, Filip M, Lourdusamy A, Kirchner P, Ekici AB, Marx LM, Suresh NP, Frischknecht R, Fejtová A, Saied EM, Arenz C, Bozec A, Wank I, Kreitz S, Heß A, Bäuerle T, Ledesma MD, Mitroi DN, Miranda AM, Oliveira TG, Gulbins E, Lenz B, Schumann G, Kornhuber J, Müller CP (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Molecular Psychiatry Springer Nature

DOI: 10.1038/s41380-021-01304-w

Abstract

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone–brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental–physical co-morbidity trias of alcohol abuse—depression/anxiety—bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental–physical co-morbidity trias.

Authors with CRIS profile

Liubov Kalinichenko Department of Psychiatry and Psychotherapy Christiane Mühle Medizinische Fakultät Felix Anderheiden Department of Paediatrics and Adolescent Medicine Anna-Lisa Eberle Professur für Suchtmedizin Martin Jürgen Hofer Professur für Suchtmedizin Sabine Huber Professur für Suchtmedizin Stefanie Kämpf Professur für Suchtmedizin Georgios Kogias Professur für Suchtmedizin Laura Lacatusu Professur für Suchtmedizin Cosima Rhein Department of Psychiatry and Psychotherapy Christina Rothballer Department of Neurology Julia Scholz Medizinische Fakultät Franziska Ulrich Professur für Suchtmedizin Florian Valenta Department of Anaesthesiology Arif Bülent Ekici Institute of Human Genetics Renato Frischknecht Lehrstuhl für Tierphysiologie Anna Fejtová Professur für Molekulare Psychiatrie Aline Bozec Juniorprofessur für Osteoimmunologie Isabel Wank Institut für Experimentelle und Klinische Pharmakologie und Toxikologie Silke Kreitz Lehrstuhl für Pharmakologie und Toxikologie Andreas Heß Lehrstuhl für Pharmakologie und Toxikologie Tobias Bäuerle Professur für Multimodale Bildgebung in der präklinischen Forschung Bernd Lenz Medizinische Fakultät Johannes Kornhuber Lehrstuhl für Psychiatrie und Psychotherapie Peter Christian Müller Professur für Suchtmedizin

Involved external institutions

Universidade do Minho PT Portugal (PT) Fudan University / 复旦大学 CN China (CN) Polska Akademia Nauk (PAN) / Polish Academy of Sciences PL Poland (PL) University College Dublin (UCD) IE Ireland (IE) Heinrich-Heine-Universität Düsseldorf DE Germany (DE) Humboldt-Universität zu Berlin DE Germany (DE) Spanish National Research Council / Consejo Superior de Investigaciones Científicas (CSIC) ES Spain (ES) Universität Duisburg-Essen (UDE) DE Germany (DE) Universität Leipzig DE Germany (DE) University of Nottingham GB United Kingdom (GB)

How to cite

APA:

Kalinichenko, L., Mühle, C., Jia, T., Anderheiden, F., Datz, M., Eberle, A.-L.,... Müller, C.P. (2021). Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects. Molecular Psychiatry. https://doi.org/10.1038/s41380-021-01304-w

MLA:

Kalinichenko, Liubov, et al. "Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects." Molecular Psychiatry (2021).

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