MAGE-D1 regulates expression of depression-like behavior through serotonin transporter ubiquitylation.
The ubiquitin-proteasome system (UPS) controls the stability of most cellular proteins. The polymorphism of UPS-related genes is associated with major depression disorder, but less is known about the molecule that plays a role in depression by modulating the UPS. Melanoma antigen gene-D1 (MAGE-D1) interacts with RING E3 ubiquitin ligase and ... is implicated in protein degradation. MAGE-D1 may thus play an important role in the CNS via ubiquitylation. Here, we clarified a novel role of MAGE-D1 in emotional functions, namely its modulation of ubiquitylation to the serotonin transporter (SERT). The MAGE-D1 knock-out and knockdown by small interfering RNA (siRNA) in the prefrontal cortex showed depression-like behavior, such as a decrease in exploratory behavior in both the home cage and novel apparatus, a decrease in social interaction, increased immobility time during forced swimming and tail suspension, and a decrease in sucrose preference without any anxiety, or cognitive or motor dysfunction. Acute and chronic (28 d) administration of sertraline (10 mg/kg) and imipramine (20 mg/kg) reversed all or part of depression-like behavior in knock-out mice. In these mice, the serotonergic function in the prefrontal cortex and hippocampus was hypoactive, accompanied by hyperexpression of SERT attributable to a decrease in ubiquitylation. Furthermore, MAGE-D1 binds to SERT via the necdin homology domain. MAGE-D1 overexpression in cells resulted in a decrease in serotonin uptake activity and the protein level of SERT but an increase in ubiquitylated SERT. Together, the present findings suggest a novel role for MAGE-D1 in depressive behaviors: modulating SERT ubiquitylation.
Mesh Terms:
Animals, Antidepressive Agents, Antigens, Neoplasm, Behavior, Animal, Brain, CHO Cells, Cricetinae, Depression, Female, Gene Knockdown Techniques, Imipramine, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microinjections, Neoplasm Proteins, Protein Binding, RNA, Small Interfering, Serotonin, Serotonin Plasma Membrane Transport Proteins, Sertraline, Ubiquitination
Animals, Antidepressive Agents, Antigens, Neoplasm, Behavior, Animal, Brain, CHO Cells, Cricetinae, Depression, Female, Gene Knockdown Techniques, Imipramine, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microinjections, Neoplasm Proteins, Protein Binding, RNA, Small Interfering, Serotonin, Serotonin Plasma Membrane Transport Proteins, Sertraline, Ubiquitination
J. Neurosci.
Date: Mar. 28, 2012
PubMed ID: 22457503
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