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.
Highlights
Mental disorders are considered to be brain disorders arising from biological malfunctions in the central nervous system
1234567890();,: RESULTS neutral sphingomyelinase-2 (NSM) activity is enhanced in patients with alcohol use disorder Searching for blood markers of alcohol addiction in humans, we measured serum NSM activity of early-abstinent male and female patients diagnosed with alcohol use disorder upon hospital admission for detoxification treatment
This observation suggests an involvement of NSM in alcohol addiction
Summary
Mental disorders are considered to be brain disorders arising from biological malfunctions in the central nervous system. In clinical reality virtually all mental disorders show a high co-morbidity with peripheral organ dysfunctions. Alcohol abuse frequently co-occurs with affective disorders, such as major depression and anxiety disorders [2]. It is Received: 7 July 2021 Revised: 6 September 2021 Accepted: 9 September 2021 often accompanied by physical diseases, such as osteoporosis [3]. All three disorders are highly comorbid and may represent a co-morbidity symptom trias with distinct mental and physical dimensions [4]. We test the hypotheses that naturally occurring variations in the activity of the enzyme neutral sphingomyelinase-2 (NSM) may be a common origin of the clinically highly relevant co-morbidity trias of alcohol abuse, major depression and bone defects. We used genetic and pharmacological animal models of reduced NSM activity to investigate how this would give rise to single symptoms of either alcohol abuse, emotional dysfunction, or bone mineralisation defects
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