Genetic Deletion of Trace-Amine Associated Receptor 9 (TAAR9) in Rats Leads to Decreased Blood Cholesterol Levels.

Ramilya Z Murtazina,Larisa G Kubarskaya,Evgeniya V Efimova,Anastasia N Vaganova,Savelii R Kuvarzin,Sergey A Apryatin,Ilya S Zhukov,Elena A Popova,Olga M Korenkova,Ekaterina G Batotsyrenova,Ekaterina A Zolotoverkhaya,Natalia V Alenina,Raul R Gainetdinov

doi:10.3390/ijms22062942

Abstract

In the last two decades, interest has grown significantly in the investigation of the role of trace amines and their receptors in mammalian physiology and pathology. Trace amine-associated receptor 9 (TAAR9) is one of the least studied members of this receptor family with unidentified endogenous ligands and an unknown role in the central nervous system and periphery. In this study, we generated two new TAAR9 knockout (TAAR9-KO) rat strains by CRISPR-Cas9 technology as in vivo models to evaluate the role of TAAR9 in mammalian physiology. In these mutant rats, we performed a comparative analysis of a number of hematological and biochemical parameters in the blood. Particularly, we carried out a complete blood count, erythrocyte osmotic fragility test, and screening of a panel of basic biochemical parameters. No significant alterations in any of the hematological and most biochemical parameters were found between mutant and WT rats. However, biochemical studies revealed a significant decrease in total and low-density lipoprotein cholesterol levels in the blood of both strains of TAAR9-KO rats. Such role of TAAR9 in cholesterol regulation not only brings a new understanding of mechanisms and biological pathways of lipid exchange but also provides a new potential drug target for disorders involving cholesterol-related pathology, such as atherosclerosis.

Highlights

A total of 31 embryos microinjected with single guide RNA (sgRNA) and Cas9 mRNA were implanted to foster mothers that resulted in the birth of 17 founder offspring, which were analyzed for edits
We further investigated if cholesterol (LDLC) or high-density lipoprotein cholesterol (HDLC) have contributed to low-density lipoprotein cholesterol (LDLC) or high-density lipoprotein cholesterol the drop in cholesterol levels
To understand the role of Trace amine-associated receptor 9 (TAAR9) in mammalian physiology, in this study, we focused on the evaluation

Summary

Introduction

Trace amine-associated receptors (TAARs) are a family of monoamine-related Gprotein coupled receptors (GPCRs) discovered in 2001 by two independent groups of researchers [1,2]. They are represented by nine genes of members of this family in mammals but three of them are pseudogenes. TAAR1 is the most investigated member of the family with well-established expression in the brain and certain tissues in the periphery and is known to contribute to various CNS effects [3,4]. In 2019, the first drug based on TAAR1 agonism successfully passed Phase II of clinical trials for the treatment of schizophrenia [5]

Methods

Results

Conclusion