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

Research output: Contribution to journalArticle

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Abstract

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
Volume32
Issue number13
DOIs
Publication statusPublished - 28-03-2012
Externally publishedYes

Fingerprint

Melanoma-Specific Antigens
Serotonin Plasma Membrane Transport Proteins
Ubiquitination
Depression
Genes
Proteasome Endopeptidase Complex
Ubiquitin
Prefrontal Cortex
Hindlimb Suspension
Sertraline
Gene Knockout Techniques
Exploratory Behavior
Ubiquitin-Protein Ligases
Imipramine
Interpersonal Relations
Knockout Mice
Small Interfering RNA
Proteolysis
Sucrose
Hippocampus

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Mouri, Akihiro ; Sasaki, Aya ; Watanabe, Ken ; Sogawa, Chiharu ; Kitayama, Shigeo ; Mamiya, Takayoshi ; Miyamoto, Yoshiaki ; Yamada, Kiyofumi ; Noda, Yukihiro ; Nabeshima, Toshitaka. / MAGE-D1 regulates expression of depression-like behavior through serotonin transporter ubiquitylation. In: Journal of Neuroscience. 2012 ; Vol. 32, No. 13. pp. 4562-4580.
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abstract = "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.",
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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, vol. 32, no. 13, pp. 4562-4580. https://doi.org/10.1523/JNEUROSCI.6458-11.2012

MAGE-D1 regulates expression of depression-like behavior through serotonin transporter ubiquitylation. / Mouri, Akihiro; Sasaki, Aya; Watanabe, Ken; Sogawa, Chiharu; Kitayama, Shigeo; Mamiya, Takayoshi; Miyamoto, Yoshiaki; Yamada, Kiyofumi; Noda, Yukihiro; Nabeshima, Toshitaka.

In: Journal of Neuroscience, Vol. 32, No. 13, 28.03.2012, p. 4562-4580.

Research output: Contribution to journalArticle

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T1 - MAGE-D1 regulates expression of depression-like behavior through serotonin transporter ubiquitylation

AU - Mouri, Akihiro

AU - Sasaki, Aya

AU - Watanabe, Ken

AU - Sogawa, Chiharu

AU - Kitayama, Shigeo

AU - Mamiya, Takayoshi

AU - Miyamoto, Yoshiaki

AU - Yamada, Kiyofumi

AU - Noda, Yukihiro

AU - Nabeshima, Toshitaka

PY - 2012/3/28

Y1 - 2012/3/28

N2 - 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.

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