Journal Article

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

Sauer, Christina, Bäuerle, Tobias, Hohenschild Julia, Tay, Nicole, An-Li, Wang, Eulenburg Volker, Praetner Marc, Gulbins Erich, Abdel-Hafiz Laila, Lugmair Charlotte, Meixner, Doris, Frischknecht Renato, Lourdusamy Anbarasu, Anderheiden Felix, Granzow Jonas, Müller, Christian P, Mühle Christiane, Mbu, Taku Stephen, Tesch, Nina, Huston, Joseph P, Hess, Andreas, Lenz, Bernd, Jia Tianye, Kornhuber Johannes, Hofer, Martin, Mitroi, Daniel N, Kalinichenko, Liubov S, Werner, Markus, Mc Veigh Conor J, Kirchner Philipp, Saied, Essa M, Arenz Christoph, Kogias Georgios, Suresh, Neeraja Puliparambil, Bozec Aline, Huber, Sabine E, Frankowska Malgorzata, Fejtova Anna, Weigand, Esther, Smaga Irena, Wank, Isabel, Miranda, André M, Lacatusu Laura, Ulrich, Franziska, Datz, Maria, Kämpf Stefanie, Rhein Cosima, Valenta Florian, Marx, Lena M, Eberle Anna-Lisa, Scholz, Jessica, Kreitz Silke, Ledesma, Maria Dolores, Haase, Jana, Schumann Gunter, Ekici, Arif B, Oliveira, Tiago G, Filip Malgorzata

2021

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Abuse / Alcohol / Alcohol abuse / Association analysis / Drug abuse / Emotional behavior / Genetic analysis / Haplotypes / Hippocampus / Mental depression / Mental disorders / Mineralization / Morbidity / Neural coding / Neural networks / Osteocalcin / Signal transduction / Sphingomyelin phosphodiesterase