title: MAGE-D1 regulates expression of depression-like behavior through serotonin transporter ubiquitylation.
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.
authors.affiliation: Department of Chemical Pharmacology, Meijo University Graduate School of Pharmaceutical Sciences, Nagoya 468-8503, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Mouri
authors.forename: Aya
authors.initials: A
authors.lastname: Sasaki
authors.forename: Ken
authors.initials: K
authors.lastname: Watanabe
authors.forename: Chiharu
authors.initials: C
authors.lastname: Sogawa
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kitayama
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Mamiya
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Noda
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000502:physiology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003863:Depression / Q000188:drug therapy*; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods / Q000523:psychology; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D020280:Sertraline / Q000494:pharmacology; D054875:Ubiquitination
chemical_list: D000928:Antidepressive Agents; D000951:Antigens, Neoplasm; C120897:MAGED1 protein, human; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D007099:Imipramine; D020280:Sertraline