Scientists hope that the first ever view of an anxiety-linked protein’s crystal structure may lead to a new, improved class of drugs to treat the disorder.
Researchers from Michigan State University (MSU) have published in the journal Science details of the atomic structure of the TSPO protein. As TSPO is associated with several anxiety disorders, the scientists hope that new drug targets may be identified as a result of mapping the protein.
TSPO was discovered in 1977, during studies investigating the potential for Valium to control anxiety symptoms. However, the protein was largely dismissed as “a peripheral binding site” and was not investigated further as a potential drug target.
However, TSPO has some interesting properties that have proved beneficial to medicine. For instance, high levels of the protein are found in damaged tissue – a discovery that has been put to practical use in positive emission tomography (PET). Here, TSPO assists in imaging areas of inflammation in the brain as its presence in high concentrations indicates damaged tissue.
Now, for the first time, the MSU researchers have created a molecular-level image of TSPO’s crystal structure using X-rays.
As a result, scientists now have a greater understanding of the interactions the protein has with cholesterol – a relationship known to influence the creation of steroid hormones. The MSU team has found that TSPO plays a key role in transporting cholesterol into the “powerhouse” of cells – mitochondria – where the cholesterol is converted into essential steroid hormones.
In addition, the team identified a TSPO mutant, which the researchers describe as “an important breakthrough.” This TSPO mutation – which binds less strongly to cholesterol because of its “ridged” structure – has also been found to be associated with bipolar disorder.
The researchers believe the substantially different structure of the mutation could be a clue as to why the mutant form is strongly associated with anxiety disorders.
Study co-author Shelagh Ferguson-Miller describes the team’s findings:
“Many other scientists have studied this protein, but what exactly it is doing has been very difficult to determine. Drugs and other compounds bind to TSPO, but without knowing the structure, their effects are hard to interpret. Now that we’ve obtained the structure, it could provide important clues regarding anxiety disorders and the basis for a new generation of anti-anxiety drugs.”
However, the TSPO in the study came from bacteria rather than humans. The researchers aim to work with the pure human protein in the future, but claim that getting enough of the protein from human cells to conduct such investigations is difficult.
“One reason that TSPO’s function has been so hard to pin down is that many studies have been done in the complex and diverse environments of whole cells and tissues,” comments Fei Li, MSU postdoctoral researcher and co-author, “where a clear-cut interpretation of the results is difficult.”
“We were able to obtain a pure protein that was still functional, but isolated from these complications,” Li says.
In 2014, researchers investigated TSPO as a biomarker that could form the basis of the first noninvasive test for heart inflammation. That study suggested that TSPO “appears to be much more than a simple biomarker,” explaining that rather than simply providing a “snapshot” of inflammation levels, the protein may actually drive disease.