Research can lead to better understanding the causes of schizophrenia

For decades, psychiatrists have treated schizophrenia patients without a good understanding of the genetic causes of the debilitating disease. Recently, however, in a series of discoveries hailed as "a landmark event in the history of psychiatry," geneticists have identified several genes that appear to increase one’s risk of developing schizophrenia. Now, a new discovery by a University of Missouri-Columbia researcher strengthens the hypothesis that mutations in one of these genes cause individuals to be susceptible to the costly disease that affects approximately 1 percent of the U.S. population.

Using X-ray crystallography, an experimental research technique that provides high-resolution images of biological molecules, Jack Tanner, associate professor of Chemistry and Biochemistry at MU, has illustrated genetic mutations that geneticists believe are associated with schizophrenia.

"What we found is that some of these genetic mutations affect amino acids in the business end of the protein," said Tanner. "Thus, there appears to be a direct connection between mutations in the gene and the function of the protein."

Genes are the DNA blueprints for proteins, and proteins are the workhorse molecules of life, said Tanner. His research team focuses on proline dehydrogenase, the protein encoded by one of these genes believed to be associated with schizophrenia. X-ray crystallography allowed Tanner’s group to obtain high-resolution images of the protein’s three-dimensional architecture. The diffraction pattern of the molecule taken from the X-ray crystallography helped Tanner construct a detailed image that precisely illustrates where mutations reside on the molecule.

Tanner says the "business end" of the protein is another way of saying "the active site," an expression biochemists use to describe the region of the protein molecule where chemistry – or enzymatic function – occurs. In healthy individuals, the lack of mutations in the proline dehydrogenase gene means the enzyme functions normally. However, for some individuals who suffer with schizophrenia, the mutations linked to the disease appear to cause a malfunctioning of the enzyme by disrupting the active site structure, which likely leads to a build-up of proline in the brain.

"It’s a very exciting time in the field right now because there have been some important discoveries of several schizophrenia susceptible genes," says Jack Tanner.

Tanner’s research results were recently published in Nature Structural Biology. [ abstract ]

2003

Additional links:

Tanner Group
Chemistry Department
Biochemistry Department

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