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Translocator Protein (TSPO) Structure To Spur New Treatments For Anxiety

Michigan State University (MSU) researchers recently published new data in the journal “Science” providing a first ever look at the crystallized structure of translocator protein (TSPO) (18kDa). Translocator protein is located within the outer portion of the mitochondrial membrane. Its primary function is to transport cholesterol within mitochondria, which then is utilized to produce steroids.

TSPO was discovered originally in 1977 and initially described as a “peripheral benzodiazepine receptor,” due to the fact that it serves as a binding site for Valium. Further investigation proved that TSPO wasn’t a peripheral benzo receptor, rather was a receptor found throughout the entire brain and body. Mutations of the TSPO gene are thought to cause various types of anxiety disorders and possibly certain aspects of bipolar disorder.

Michigan State Unravels Crystal Structure of TSPO Protein

The fact that TSPO is associated with various mental illnesses, getting a better understanding of its molecular structure could lead to improved treatments for people with anxiety. A team of researchers from Michigan State University (MSU) made a breakthrough in the scientific study of TSPO. They used X-rays to produce a molecular image of TSPO’s crystal structure.

This research went on to be published in the journal “Science.” Although many researchers had studied TSPO protein in the past, they had never been able to specifically develop an image of its molecular structure; this is the first time its been done. The molecular imaging of TSPO show researchers the specific mechanisms by which the protein interacts with cholesterol, as well as other influences it may have on the creation of various steroid hormones.

As was mentioned, TSPO transports cholesterol within mitochondria, and the cholesterol gets converted into endogenous steroids. These steroids are necessary for an array of physiological functions. Mutations of the TSPO could alter production of both mitochondrial function and ultimately steroid production.

  • Source: http://www.sciencemag.org/content/347/6221/555.full

Benefits of translocator protein research

Researchers know that mutations of the TSPO protein means poorer binding with cholesterol. A specific mutation makes the TSPO more “rigid” and the rigidity of the molecular structure may be influencing various aspects of anxiety disorders, bipolar disorder, and other mental illnesses. There are numerous potential benefits to be obtained from better understanding the way TSPO mutations influence physiology.

  • Anxiety disorders: It is known that TSPO mutations may play a direct role in determining whether someone experiences an anxiety disorder. By identifying these specific mutations, it could give rise to a new class of medications that correct the mutations. For example, the compound “XBD173” (a TSPO ligand) is known to enhance neurotransmission of GABA – which promotes calmness. Many TSPO ligands are under development for the treatment of anxiety.
  • Bipolar disorder: There is some evidence suggesting that TSPO may also contribute to bipolar disorder. New research may shed some light on specific mutations that may take hold in order for a person to develop the disorder. It may also help researchers come up with new treatments for those with bipolar disorder and/or comorbid anxiety.
  • Drug development: Many drugs and compounds bind to TSPO. Without knowing the exact structure of the TSPO, it’s difficult to predict their effects. Now that we have the potential to analyze TSPO’s molecular structure, it should help give pharmaceuticals a blueprint for designing new anxiolytics.
  • Gene therapy: Scientists may be able to come up with various gene therapies in the future to target mutations of the TSPO protein expression. This may lead to treatment based on individual polymorphisms. This will likely be a therapy option in the far future for those with abnormal “rigid” molecular forms.
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22923187

List of TSPO’s Functions/Uses

Listed below are common functions of the TSPO protein as well as how it is used by researchers.  Keep in mind that there are likely significantly more functions and/or uses than the ones listed here.

  • Biomarker: In research, TSPO is commonly used in brain scans (PET) to identify areas of damage. In areas with significant damage, there tends to be elevated levels of TSPO. It is also sometimes used as a biomarker to identify heart inflammation.
  • Binding: Within the brain, TSPO is capable of binding to a variety of benzodiazepines and similar drugs. It is known to be a peripheral benzodiazepine receptor, which means that it has potential to influence GABAergic function within the brain.
  • Cholesterol: TSPO is most frequently described as a protein that is responsible for transporting cholesterol across mitochondrial membranes. This is a very important function and perhaps what TSPO is best known for.
  • Heart: It tends to interact with voltage-dependent calcium channels, meaning it helps regulate heart rate. Specifically it alters cardiac action potentials and is considered “cardio-protective.” It can help limit harmful inflammation of the heart.
  • Steroid production: It is believed to be indirectly involved in the endogenous production and synthesis of steroids. Although the evidence is somewhat controversial, some would argue that mutated TSPO proteins can lead to imbalances in the body’s steroid production.

Past research involving TSPO protein

In the past, numerous scientists had studied this particular protein, but struggled to understand its exact functions. Researcher Fei Li suggested, “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 where a clear-cut interpretation of the results is difficult.” Without knowing the structural composition of TSPO, it’s tough to predict how certain drugs would influence it.

Now that researchers have a relatively clear perspective of its molecular structure, it may be help to predict the effects of various anti anxiety medications. In fact, some believe that pharmaceutical companies may be able to analyze the molecular structure of TSPO and tailor new anxiolytics to target various mutations. A researcher from MSU stated that the findings could be a “basis for a new generation of anti-anxiety drugs.”

Final thoughts on TSPO protein breakthrough…

Although this is a significant step in the right direction for getting a better understanding of TSPO, we first need to get a better understanding of the human molecular structure rather than that from bacteria. This should help offer insight in regards to how polymorphisms of TSPO could contribute to psychiatric disorders such as anxiety and bipolar disorder. Understanding of its molecular structure could also provide pharmaceutical companies with new information they need to create superior anxiolytic medications (benzodiazepines are linked to dementia).

Fortunately, the researchers have made plans to conduct follow-up studies with human TSPO to investigate how it may be influencing the development of anxiety disorders. This was the first time ever that they were able to obtain a pure TSPO protein that was isolated and retained functionality. In addition to helping with the development of new treatments for mental illness, the research may provide insight as to how TSPO is related to heart-inflammation and brain injuries.

Most people reading this website will probably be excited to know that there is constant research in the works to get a better understanding of the human body, various proteins, etc. – much of which could offer much-needed insights towards improving treatments for mental illness. While it may be a longshot from now until the FDA passes a pharmaceutical drug tailored to target TSPO, and an even longer shot from gene or protein therapy to correct TSPO polymorphisms, any advancement is a step in the right direction.

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