It’s a case of mistaken identity: A protein long assumed to be essential to the production of steroids, including testosterone, estrogen and the primary stress hormone cortisol, isn’t necessary at all. A new study challenges the status quo in the science of hormones, debunking long-held assumptions about a pivotal protein and opening the door for better diagnosis and treatment of steroid hormone disorders.

The research, led by assistant professor of animal science Vimal Selvaraj with colleagues from the University of California, Davis, was published online Oct. 30 in the journal Endocrinology.

The researchers tested the function of a protein – called translocator protein (TSPO) – that has long been associated with playing an essential role when cells manufacture steroid hormones out of cholesterol. In textbook diagrams, TSPO is the gatekeeper, hoisting cholesterol across a membrane and into the cell’s mitochondria as the crucial first step. Selvaraj is keenly interested in understanding its function, because it is also present in high amounts in cancer cells, the brain lesions caused by multiple sclerosis and in stroke-damaged tissues. But Selvaraj questioned whether TSPO functioned as assumed.

“This protein has been extensively studied, which is documented in more than 700 research papers, and for over 25 years, it has been assumed to be essential to steroid production in mammals,” Selvaraj said. “I was suspicious, in part because it is present in so many tissues that don’t produce steroids.”

Other researchers had shown that without the protein, mouse embryos cannot survive. This made it particularly difficult to study, and for decades research focused on its activity in cells grown in petri dishes. Selvaraj and his colleagues wanted a definitive assessment of its function, and that required looking at a whole, living organism – in this case, mice – rather than cells.

To do this, they developed lines of mice that lacked the protein in the testis, the site of all testosterone production. Using genetics with surgical precision, they created mice in which the gene for the protein was deleted in the Leydig cells, which make testosterone. They measured the effects on testosterone production and reproductive success of the protein-deficient mice. Without the gene, male mice produced normal amounts of testosterone and showed no differences in mating and litter sizes.

“This discovery rectifies a huge misconception in the field of endocrinology,” Selvaraj said. “These findings will force scientists to reexamine conclusions drawn from numerous peer-reviewed studies of steroid hormone biosynthesis.”

While the field updates its understanding and rebuilds a model without TSPO for cholesterol transport into the mitochondria, for Selvaraj the interesting question is what the TSPO protein actually does. It is considered a biomarker for many neurological disorders and inflammation, including physical brain trauma, Huntington’s disease and multiple sclerosis. Because it is in all the “right” places for these neurological diseases, detection tools can use it as a targeting beacon to deliver markers with cellular accuracy. Moreover, Selvaraj and colleagues have previously demonstrated that TSPO is in fact a therapeutic target for ameliorating disease severity in a mouse model for multiple sclerosis.

Understanding TSPO’s function also will have ramifications across the tree of life. According to Selvaraj, the protein is present in organisms from bacteria to humans, and the protein’s shape and functional regions are highly conserved. The protein is so similar across species that the gene from a rat functions correctly in a bacteria, where the protein regulates photosynthesis in response to oxygen.

“We’re now on a journey to find out what TSPO really does. When we get there, it will really advance our understanding of cancer and neuropathology,” said Selvaraj.

The paper is titled “Translocator Protein/Peripheral Benzodiazepine Receptor Is Not Required for Steroid Hormone Biosynthesis.”

Amanda Garris, Ph.D. ’04, is the agricultural experiment stations communications officer for the College of Agriculture and Life Sciences.