MAGE-D1 regulates expression of depression-like behavior through serotonin transporter ubiquitylation

Akihiro Mouri, Aya Sasaki, Ken Watanabe, Chiharu Sogawa, Shigeo Kitayama, Takayoshi Mamiya, Yoshiaki Miyamoto, Kiyofumi Yamada, Yukihiro Noda, Toshitaka Nabeshima

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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.

Original languageEnglish
Pages (from-to)4562-4580
Number of pages19
JournalJournal of Neuroscience
Issue number13
Publication statusPublished - 28-03-2012

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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    Mouri, A., Sasaki, A., Watanabe, K., Sogawa, C., Kitayama, S., Mamiya, T., Miyamoto, Y., Yamada, K., Noda, Y., & Nabeshima, T. (2012). MAGE-D1 regulates expression of depression-like behavior through serotonin transporter ubiquitylation. Journal of Neuroscience, 32(13), 4562-4580.