TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis

Owen, David R, Fan, Jinjiang, Campioli, Enrico, Venugopal, Sathvika, Midzak, Andrew, Daly, Edward, Harlay, Aline, Issop, Leeyah, Libri, Vincenzo, Kalogiannopoulou, Dimitra, Oliver, Eduardo, Gallego-Colon, Enrique, Colasanti, Alessandro, Huson, Les, Rabiner, Ilan, Suppiah, Puvan, Essagian, Charles, Matthews, Paul M and Papadopoulos, Vassilios (2017) TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis. Biochemical Journal. ISSN 0264-6021

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Abstract

The 18 kDa translocator protein (TSPO) is a ubiquitous conserved outer mitochondrial membrane protein implicated in numerous cell and tissue functions, including steroid hormone biosynthesis, respiration, cell proliferation and apoptosis. TSPO binds with high affinity to cholesterol and numerous compounds, is expressed at high levels in steroid-synthesizing tissues, and mediates cholesterol import into mitochondria, which is the rate-limiting step in steroid formation. In humans, the rs6971 polymorphism on the TSPO gene leads to an amino acid substitution in the fifth transmembrane loop of the protein, which is where the cholesterol-binding domain of TSPO is located, and this polymorphism has been associated with anxiety-related disorders. However, recent knockout mouse models have provided inconsistent conclusions of whether TSPO is directly involved in steroid synthesis. In this report, we show that TSPO deletion mutations in rat and its corresponding rs6971 polymorphism in humans alters adrenocorticotropic hormone (ACTH)-induced plasma corticosteroid concentrations. Rat tissues examined show
increased cholesteryl ester accumulation, and neurosteroid formation was abolished in homozygous rats. These results also support a role for TSPO ligands in diseases with steroiddependent stress and anxiety elements.

Item Type: Article
Keywords: Translocator protein, rats, humans, lipid droplets, cholesterol transport, steroids
Schools and Departments: Brighton and Sussex Medical School > Neuroscience
Depositing User: Alexei Fisk
Date Deposited: 09 Nov 2017 10:10
Last Modified: 09 Nov 2017 10:13
URI: http://sro.sussex.ac.uk/id/eprint/71085

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