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, Yukio; Yamada, Kiyofumi; Noda, Yukihiro; Nabeshima, Toshitaka

doi:10.1523/jneurosci.6458-11.2012

Cited by 76 publications

(96 citation statements)

References 84 publications

(108 reference statements)

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“…As such, the changes in 5-HTT BP ND observed in vivo using [ 11 C]DASB PET reflect greater availability of the 5-HTT to clear serotonin from extracellular space in the winter, thereby lowering levels of extracellular serotonin. This is a key issue, given that overexpression of 5-HTT in the PFC is associated with decreased stimulation-induced release of 5-HT from serotonergic neurons and differential expression of the 5-HTT is associated with magnitude of response to anxiogenic stimuli (Jennings et al, 2010;Lesch et al, 1996;Mouri et al, 2012). In addition, while greater seasonal variation in [ ]DASB 5-HTT BP ND levels, themselves.…”

Section: Severe Sadmentioning

confidence: 99%

“…The 5-HTT is also an important target for controlling affect given that polymorphisms in the 5-HTT promoter are associated with risk toward MDD, medications that affect the 5-HTT influence both cognitive recall of emotionally valent material and negative cognitive interpretations of life events; and that overexpression of 5-HTT in regions controlling affect are associated with depressive behaviors in rodents (Caspi et al, 2010;Harmer et al, 2004;Line et al, 2014;Meyer et al, 2003;Mouri et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…We prioritized the PFC and ACC as these regions had considerable seasonal variation in previous study, contain structures with key roles in mood regulation and cognitive processing of emotion, and are the regions for which 5-HTT overexpression is associated with depressive behaviors (Line et al, 2014;Mouri et al, 2012;PraschakRieder et al, 2008;Ressler and Mayberg, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Increased Seasonal Variation in Serotonin Transporter Binding in Seasonal Affective Disorder

Tyrer

Levitan

Houle

et al. 2016

Neuropsychopharmacol

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Seasonal affective disorder (SAD) is highly prevalent with rates of 1-6% and greater prevalence at more extreme latitudes; however, there are almost no direct brain investigations of this disorder. In health, serotonin transporter binding potential (5-HTT BP ND ), an index of 5-HTT levels, is greater throughout the brain in fall-winter compared with spring-summer. We hypothesized that in SAD, this seasonal variation would be greater in brain regions containing structures that regulate affect such as the prefrontal and anterior cingulate cortices (PFC and ACC). Furthermore, given the dimensional nature of SAD symptoms, it was hypothesized that seasonal fluctuation of 5-HTT BP ND in the PFC and ACC would be greatest in severe SAD. Twenty SAD and twenty healthy participants underwent [11 C]DASB positron emission tomography scans in summer and winter to measure seasonal variation in [ 11 C]DASB 5-HTT BP ND . Seasonal increases in [11 C]DASB 5-HTT BP ND were greater in SAD compared with healthy in the PFC and ACC, primarily due to differences between severe SAD and healthy (severe SAD vs healthy; Mann-Whitney U, U = 42.5 and 37.0, p = 0.005 and 0.003, respectively; greater magnitude in severe SAD of 35.10 and 14.23%, respectively), with similar findings observed in other regions (U = 40.0-62.0, p = 0.004-0.048; greater magnitude in severe SAD of 13.16-17.49%). To our knowledge, this is the first brain biomarker identified in SAD. This creates a new opportunity for phase 0 studies to target this phenotype and optimize novel prevention/treatment strategies for SAD.

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Section: Severe Sadmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Increased Seasonal Variation in Serotonin Transporter Binding in Seasonal Affective Disorder

Tyrer

Levitan

Houle

et al. 2016

Neuropsychopharmacol

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“…7,9,25 In the study, NRAGE negatively regulated the polyubiquitination of both RNF8 and BARD1. Notably, unlike PCNA, either RNF8 or BARD1 could dramatically reverse the cell survival of NRAGE-deficient EC , and RNF8 expression in the serial dissections of esophageal T tissues (T1, T2).…”

Section: Discussionmentioning

confidence: 94%

“…(KO) mice exhibit depression-like behavior 9 and disorder in circadian clock, 10 both of which are analogous to DDR defective scenarios. 11,12 However, to our knowledge, there has been no direct report concerning the role of NRAGE in DDR.…”

Section: (3) Nrage Knockoutmentioning

confidence: 99%

NRAGE is involved in homologous recombination repair to resist the DNA-damaging chemotherapy and composes a ternary complex with RNF8–BARD1 to promote cell survival in squamous esophageal tumorigenesis

Yang

Pan

et al. 2016

Cell Death Differ

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NRAGE, a neurotrophin receptor-interacting melanoma antigen-encoding gene homolog, is significantly increased in the nucleus of radioresistant esophageal tumor cell lines and is highly upregulated to promote cell proliferation in esophageal carcinomas (ECs). However, whether the overexpressed NRAGE promotes cell growth by participating in DNA-damage response (DDR) is still unclear. Here we show that NRAGE is required for efficient double-strand breaks (DSBs) repair via homologous recombination repair (HRR) and downregulation of NRAGE greatly sensitizes EC cells to DNA-damaging agents both in vitro and in vivo. Moreover, NRAGE not only regulates the stability of DDR factors, RNF8 and BARD1, in a ubiquitin-proteolytic pathway, but also chaperons the interaction between BARD1 and RNF8 via their RING domains to form a novel ternary complex. Additionally, the expression of NRAGE is closely correlated with RNF8 and BARD1 in esophageal tumor tissues. In summary, our findings reveal a novel function of NRAGE that will help to guide personalized esophageal cancer treatments by targeting NRAGE to increase cell sensitivity to DNA-damaging therapeutics in the long run. In mammalian cells, DNA lesions are always endogenously and exogenously induced, 1 among which double-strand breaks (DSBs) are the most lethal lesions.2 Therefore, efficient DNA-damage response (DDR) is essential to maintain genomic integrity.1,3 However, DDR is a double-edged sword. In normal organisms, DDR protects cells from tumorigenesis, whereas in tumor cells, DDR enables cells to grow and resist DNA-damaging therapeutic agents. 4 Thus, in order to correctly use DDR factors in cancer diagnosis and targeted therapy, it is important to study molecular pathways underlying DDR in cancer cells. 5NRAGE is a member of the melanoma-associated antigen (MAGE) family. 6 Previous studies reveal that it is possibly a DDR factor: (1) upregulation of NRAGE in the nucleus is highly associated with the development of esophageal carcinoma (EC) by interacting with the proliferating cell nuclear antigen (PCNA); 7 (2) the level of NRAGE is significantly increased in the nucleus of radioresistant EC cells; 8 (3) NRAGE knockout (KO) mice exhibit depression-like behavior 9 and disorder in circadian clock, 10 both of which are analogous to DDR defective scenarios.11,12 However, to our knowledge, there has been no direct report concerning the role of NRAGE in DDR.In the present study, we aim to study the role and the underlying mechanisms of NRAGE in DDR. Our data support that NRAGE is a positive regulator in homologous recombination (HR) and regulates the chemoresistance of EC cells both in vivo and in vitro. From mechanism, it regulates the stability of RNF8 and BARD1 via the ubiquitin-proteasome pathway and interacts with the RING domains of the two proteins as a chaperon to form a novel ternary complex to participate in DDR. Furthermore, clinical characterization of NRAGE, RNF8, and BARD1 in squamous EC tissues shows that the expression of NRAGE protein is closely related wi...

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1‐Stearoyl‐2‐docosahexaenoyl‐phosphatidic acid interacts with and activates Praja‐1, the E3 ubiquitin ligase acting on the serotonin transporter in the brain

Lü

Murakami

et al. 2020

FEBS Letters

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Edited by Sandro SonninoSerotonin transporter (SERT) is involved in serotonergic system regulation and in the pathophysiology/therapeutics of serotonin-/SERT-related diseases such as obsessive-compulsive disorder, depression, autism, and schizophrenia. We recently revealed that diacylglycerol (DG) kinase (DGK) d induces ubiquitination/degradation of SERT in a DGK activity-dependent manner through Praja-1 E3 ubiquitin-protein ligase. However, it is still unclear how Praja-1 activity is regulated by DGKd. Here, we reveal that 1-stearoyl-2-docosahexaenoyl (18:0/22:6)-phosphatidic acid (PA) and 18:0/22:6-DG are simultaneously decreased and accumulated, respectively, in the DGKd-knockout mouse brain, indicating that DGKd selectively phosphorylates 18:0/22:6-DG to generate 18:0/22:6-PA. Moreover, we find that 18:0/22:6-PA selectively binds to Praja-1 and enhances its activity. These results strongly suggest that 18:0/ 22:6-PA generated by DGKd activates Praja-1 to degrade SERT in the brain.Keywords: diacylglycerol kinase; docosahexaenoic acid; E3 ubiquitinprotein ligase; obsessive-compulsive disorder; Praja-1; serotonin transporter Serotonin/5-hydroxytryptamine (5-HT) is known to be involved in anxiety, depression, compulsiveness, and impulsivity [1]. The serotonin/5-HT transporter (SERT) reuptakes 5-HT from the synaptic cleft into the presynaptic neuron for recycling and metabolic degradation [2,3]. Selective serotonin reuptake (SERT) inhibitors (SSRIs) are used for the treatment of obsessive-compulsive disorder (OCD) [2,3] and major depressive disorder [4]. Several studies using SERTdeficient rodents have demonstrated that SERT is implicated in neurodevelopmental disorders, such as depression, anxiety, and autism [5]. Therefore, hyperfunction of SERT, which reduces the amount of 5-HT in the synaptic cleft, causes various psychiatric disorders mentioned above. However, the regulatory mechanisms of SERT function are still obscure.Diacylglycerol (DG) kinase (DGK), which consists of ten isozymes (a-j), is a lipid-metabolizing enzyme that phosphorylates DG to generate phosphatidic acid (PA) [6][7][8][9][10]. DG and PA are established lipid second messengers that regulate a wide variety of physiological and pathological events.

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MAGE-D1 Regulates Expression of Depression-Like Behavior through Serotonin Transporter Ubiquitylation

Cited by 76 publications

References 84 publications

Increased Seasonal Variation in Serotonin Transporter Binding in Seasonal Affective Disorder

Increased Seasonal Variation in Serotonin Transporter Binding in Seasonal Affective Disorder

NRAGE is involved in homologous recombination repair to resist the DNA-damaging chemotherapy and composes a ternary complex with RNF8–BARD1 to promote cell survival in squamous esophageal tumorigenesis

1‐Stearoyl‐2‐docosahexaenoyl‐phosphatidic acid interacts with and activates Praja‐1, the E3 ubiquitin ligase acting on the serotonin transporter in the brain

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