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

Posted on July 07, 2021

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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"

Serotonin/5-hydroxytryptamine (5-HT) is known to be involved in anxiety, depression, compulsiveness, and impulsivity. The serotonin/5-HT transporter (SERT) re-uptakes 5-HT and recycles it or metabolically degrades it. Drugs called serotonin re-uptake inhibitors (SSRIs) are used to treat obsessive-compulsive disorder (OCD) as well as major depressive disorder. Studying SERT deficient mice, it has been shown that SERT is linked to neurodevelopmental disorders such as depression, anxiety, and autism. Hyperfunction of SERT causes a reduction in 5-HT in the synaptic cleft and thus causes the psychiatric disorders previously mentioned. The mechanism by which SERT function is regulated is largely obscure.

Dr. Sakane and his research group dedicate much of their time to studying diacylglycerol (DG) kinase (DGK) and its ten isozymes. They have been able to show that DGK-knockout mice showed SSRI (fluoxetine)-sensitive OCD-like behaviors and that DGK augmented the amount of SERT protein in the cerebral cortex. This strongly indicates that the increase in SERT levels leads to OCD-like behaviors in the mice. They also found that DGKδ interacted with SERT, melanoma antigen gene D1 (MAGE-D1), and Praja-1 E3 ubiquitin-protein ligase. This ligase ubiquitinates SERT in a DGK activity-dependent manner. The way that DGKδ controls Praja-1 activity is unclear but this study published by Dr. Sakane and his research group at Chiba University sheds some light on this process!

They were able to uncover that 1-stearoyl-2docosahexaenoic-(18:0/22:6)PA and 18:0/22:6-DG were simultaneously decreased and accumulated in the cerebral cortex of the DGKδ-KO mice. This indicates that DGKδ selectively phosphorylates 18:0/22:6 DG to produce 18:0/22:6 PA. The PA species then was found to interact with Praja-1 and enhance its ligase activity strongly suggesting that DGKδ activates Praja-1 via the PA species to degrade SERT.

A better understanding of this mechanism could help explain many biological processes in the brain. Docosahexaenoic acid (DHA) is regarded as important for brain development. DHA has also been reported in several instances to have anti-anxiety effects. The DHA-containing PA species that selectively binds to Praja-1, which is the ligase for SERT, is closely related to anxiety. This could explain why those effects have been noticed in DHA supplemented patients exhibiting anxiety. Other implications of the understanding of this mechanism include better treatments for major depressive disorder, OCD, schizophrenia (positive symptoms), and autism. Chemical compounds mimicking 18:0/22:6 PA could be used as therapeutics to fight these disorders. DGKδ inhibitors could be used to treat negative symptoms of schizophrenia.

In the future, Dr. Sakane’s group wants to further investigate the mechanism by which 18:/22:6 PA activates Praja-1 and whether this PA species accounts for the anti-anxiety effects of DHA. This is truly remarkable progress towards a better understanding of brain-related ailments and we are extremely proud of the work being conducted in Dr. Sakane’s research lab. Dr. Sakane takes advantage of several Avanti products for his research. If you are looking for any kind of phospholipid check our vast catalog by clicking the link below! Don’t settle for anything less than the purest lipids for your research! We can’t wait to see what our lipids can help you accomplish!

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