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

Kalinichenko, Liubov S and Mühle, Christiane and Jia, Tianye and Anderheiden, Felix and Datz, Maria and Eberle, Anna-Lisa and Eulenburg, Volker and Granzow, Jonas and Hofer, Martin and Hohenschild, Julia and Huber, Sabine E and Kämpf, Stefanie and Kogias, Georgios and Lacatusu, Laura and Lugmair, Charlotte and Taku, Stephen Mbu and Meixner, Doris and Tesch, Nina and Praetner, Marc and Rhein, Cosima and Sauer, Christina and Scholz, Jessica and Ulrich, Franziska and Valenta, Florian and Weigand, Esther and Werner, Markus and Tay, Nicole and Mc Veigh, Conor J and Haase, Jana and Wang, An-Li and Abdel-Hafiz, Laila and Huston, Joseph P and Smaga, Irena and Frankowska, Malgorzata and Filip, Malgorzata and Lourdusamy, Anbarasu and Kirchner, Philipp and Ekici, Arif B and Marx, Lena M and Suresh, Neeraja Puliparambil and et al, . (2021) Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects. Molecular Psychiatry, doi: 10.1038/s41380-021-01304-w.

External website: https://www.nature.com/articles/s41380-021-01304-w

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.

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