Window into a Disease

ORNL's CSMB and UT Medical Center collaborate to understand the molecular mechanisms behind Huntington's Disease

Among the ORNL Center for Structural Molecular Biology's most notable collaborations has been working with the University of Tennessee Medical Center, in helping to understand the molecular mechanisms behind Huntington's Disease, a genetic condition that leads to the deterioration and death of brain cells, causing problems with muscle control and certain thought processes. In its advanced stages, the disease can affect an individual's ability to walk, talk or even swallow.

Like a number of genetic diseases, Huntington's is caused by a defective protein that includes a repeated set of biochemical instructions. UT researcher Tatiana Perevozchikova explains that the toxic protein contains an unusually long string of 40 or more glutamine amino acids rather than the normal 15 or 20. The additional amino acids cause the protein to form thin, threadlike fibers, or aggregates, in the patients' brains that cause brain cells to deteriorate and die.

Thus far, researchers have not been able to determine at what stage of development these aggregates become toxic to brain cells. To gain a better understanding of this aspect of the disease, researchers are applying the BioSANS instrument's ability to analyze functioning biological systems to observe the aggregates at different stages of development. "The BioSANS instrument enables us to see the formation of aggregates over time," Perevozchikova said. "This kind of analysis is not possible with other techniques."

Perevozchikova notes that another advantage of the BioSANS instrument is its ability to study the protein molecules in solution. Because the molecules are large, flexible and change over time, scientists can use the BioSANS instrument to make detailed observations of the growth formation of the protein fibrils, as well as generating 3-D structural maps of both the proteins and the aggregates.

To date, researchers at ORNL have gathered a wealth of information about the differences between the toxic Huntington's protein and its normal counterpart, as well as the mechanisms that may produce the disease's toxic effects. Over the long term, scientists would like to learn how to control the process of aggregation or even eliminate it entirely. Evidence suggests that the aggregates do the bulk of their damage to brain cells in the aggregates' early stages of development. "If we can describe the toxic protein at this stage," says Perevozchikova, "the information could lead to the development of a therapeutic agent for treating Huntington's disease."

Further research planned at the Center for Structural Molecular Biology and on other instruments at ORNL's Spallation Neutron Source is expected to shed light on this and other questions related to finding a treatment for Huntington's Disease.

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