ERICH3: vesicular association and antidepressant treatment response

Selective serotonin reuptake inhibitors (SSRIs) are standard of care for major depressive disorder (MDD) pharmacotherapy, but only approximately half of these patients remit on SSRI therapy. Our previous genome-wide association study identified a single-nucleotide polymorphism (SNP) signal across th...

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Published in:Molecular psychiatry Vol. 26; no. 6; pp. 2415 - 2428
Main Authors: Liu, Duan, Zhuang, Yongxian, Zhang, Lingxin, Gao, Huanyao, Neavin, Drew, Carrillo-Roa, Tania, Wang, Yani, Yu, Jia, Qin, Sisi, Kim, Daniel C, Liu, Erica, Nguyen, Thanh Thanh Le, Biernacka, Joanna M, Kaddurah-Daouk, Rima, Dunlop, Boadie W, Craighead, W Edward, Mayberg, Helen S, Binder, Elisabeth B, Frye, Mark A, Wang, Liewei, Weinshilboum, Richard M
Format: Journal Article
Language:English
Published: England Nature Publishing Group 01.06.2021
Subjects:
Antidepressants
Antidepressive Agents - therapeutic use
Cell culture
Central nervous system
Clathrin
Clinical trials
Culture media
Depressive Disorder, Major - drug therapy
Depressive Disorder, Major - genetics
Drug therapy
Gene polymorphism
Genome-wide association studies
Genome-Wide Association Study
Genomes
Humans
Immunofluorescence
Isoforms
Lysates
Mental depression
Patients
Serotonin - therapeutic use
Serotonin uptake inhibitors
Serotonin Uptake Inhibitors - therapeutic use
Single-nucleotide polymorphism
Systematic review
ISSN:1359-4184, 1476-5578, 1476-5578
Online Access:Get full text
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Summary:Selective serotonin reuptake inhibitors (SSRIs) are standard of care for major depressive disorder (MDD) pharmacotherapy, but only approximately half of these patients remit on SSRI therapy. Our previous genome-wide association study identified a single-nucleotide polymorphism (SNP) signal across the glutamate-rich 3 (ERICH3) gene that was nearly genome-wide significantly associated with plasma serotonin (5-HT) concentrations, which were themselves associated with SSRI response for MDD patients enrolled in the Mayo Clinic PGRN-AMPS SSRI trial. In this study, we performed a meta-analysis which demonstrated that those SNPs were significantly associated with SSRI treatment outcomes in four independent MDD trials. However, the function of ERICH3 and molecular mechanism(s) by which it might be associated with plasma 5-HT concentrations and SSRI clinical response remained unclear. Therefore, we characterized the human ERICH3 gene functionally and identified ERICH3 mRNA transcripts and protein isoforms that are highly expressed in central nervous system cells. Coimmunoprecipitation identified a series of ERICH3 interacting proteins including clathrin heavy chain which are known to play a role in vesicular function. Immunofluorescence showed ERICH3 colocalization with 5-HT in vesicle-like structures, and ERICH3 knock-out dramatically decreased 5-HT staining in SK-N-SH cells as well as 5-HT concentrations in the culture media and cell lysates without changing the expression of 5-HT synthesizing or metabolizing enzymes. Finally, immunofluorescence also showed ERICH3 colocalization with dopamine in human iPSC-derived neurons. These results suggest that ERICH3 may play a significant role in vesicular function in serotonergic and other neuronal cell types, which might help explain its association with antidepressant treatment response.
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ISSN:1359-4184
1476-5578
1476-5578
DOI:10.1038/s41380-020-00940-y