ERICH3: vesicular association and antidepressant treatment response.

Autor: Liu D; Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Zhuang Y; Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Rubedo Life Sciences, Sunnyvale, CA, USA., Zhang L; Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Gao H; Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Neavin D; Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia., Carrillo-Roa T; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany., Wang Y; Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Xi'an No.1 Hospital, the First Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China.; Shaanxi Institute of Ophthalmology, Shaanxi Key Laboratory of Ophthalmology, Shaanxi Clinical Research Center for Ophthalmology Diseases, Xi'an, Shaanxi, China., Yu J; Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Qin S; Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Kim DC; Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Liu E; Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Nguyen TTL; Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Biernacka JM; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA., Kaddurah-Daouk R; Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.; Department of Medicine, Duke University, Durham, NC, USA.; Duke Institute for Brain Sciences, Duke University, Durham, NC, USA., Dunlop BW; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA., Craighead WE; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA., Mayberg HS; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.; Departments of Neurology and Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Binder EB; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA., Frye MA; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA., Wang L; Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Weinshilboum RM; Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. Weinshilboum.Richard@mayo.edu.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2021 Jun; Vol. 26 (6), pp. 2415-2428. Date of Electronic Publication: 2020 Nov 23.
DOI: 10.1038/s41380-020-00940-y
Abstrakt: 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.
(© 2020. The Author(s).)
Databáze: MEDLINE
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