Scientists have confirmed that the protein DISC1 takes part in multiple interactions within the neurons of the brain and influences significant processes such as cell division and growth – that means many downstream effects can occur if the protein is acting abnormally.
While earlier research identified Schizophrenia 1 (DISC1) as the gene responsible for encoding this brain protein, there are many questions that remain, and the U of S researchers are working to solve one of its biggest mysteries: What does DISC1 look like?
“Everything is about shape,” says Dr. Adelaine Leung an assistant professor in the Department of Veterinary Biomedical Sciences at the Western College of Veterinary Medicine (WCVM) who has focused her scientific research on the field of structure-based drug design. “You need to understand the shape to fully understand the function.”
Health problems and disease arise when there are incompatible changes in the shape of proteins. For example, if a protein’s job is to relocate within the cell or interact with another component, serious implications can arise if a mutation changes that shape.
Leung theorizes that once scientists are able to design therapeutic drugs that bind to the DISC1 protein specifically, they will be able to regulate the action of the protein and potentially reduce the symptoms of the psychiatric illness – but first they need to know the shape of the protein.
That’s why Leung and her research team are working to determine the structure of the DISC1 protein – a known psychiatric risk factor. But how can they see such a miniscule structure?
“We use a technique called ‘X-ray crystallography’ because we are interested in atomic resolution,” Leung explains. “We want to see atom-to-atom arrangement of the molecule.”
A crystal is a pure, highly ordered sample which looks similar to the crystal shape of a diamond, only on a microscopic scale. When beams of X-rays interact with the crystal, the scientists are able to produce a 3D image by using computers and mathematical principles.
Until now DISC1 has been challenging to work with – the protein is not extensively characterized and it’s troublesome to work with biochemically.
“A lot of people have tried and failed [to structure this protein],” says Leung. “In order to get crystals, they have to be in the same orientation. DISC1 inherently does not want to be in the same shape. That is the biggest challenge.”
The researchers hope to solve this problem by using one of DISC1’s interacting partners to lock it into a single shape. Since they’ve confirmed that other molecules can attach to DISC1 inside the brain, they hope to create the same interaction within a test tube.
Another possible approach would involve characterizing fragments of the protein separately and then piecing them together – a strategy similar to taking apart an engine in order to learn what the parts do.
Since DISC1 has different sub-structures known as domains, the researchers can investigate them as a means to finding out more about the stability and function of the protein. By discovering a single piece of information about a fragment, they’ll be adding one more piece to the puzzle and moving a step closer to determining the exact structure of DISC1.
Once more is known about the protein’s structure, Leung and her team can move ahead in their investigation to determine if and how variations to DISC1 can affect brain development and increase susceptibility to a variety of psychiatric diseases.
Sean Lipsit of Prince Albert, Saskatchewan, is a fourth-year biochemistry student who was part of the WCVM’s Undergraduate Summer Research and Leadership program in 2017. Sean’s story is part of a series of articles written by WCVM summer research students.