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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.
Afiliação
  • Mouri A; Department of Chemical Pharmacology, Meijo University Graduate School of Pharmaceutical Sciences, Nagoya 468-8503, Japan.
J Neurosci ; 32(13): 4562-80, 2012 Mar 28.
Article em En | MEDLINE | ID: mdl-22457503
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Depressão / Proteínas da Membrana Plasmática de Transporte de Serotonina / Antígenos de Neoplasias / Proteínas de Neoplasias Limite: Animals Idioma: En Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Depressão / Proteínas da Membrana Plasmática de Transporte de Serotonina / Antígenos de Neoplasias / Proteínas de Neoplasias Limite: Animals Idioma: En Ano de publicação: 2012 Tipo de documento: Article