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Flora Meilleur prepares protein solutions for structural investigation with neutrons. | Courtesy of ORNL Flickr / Jason Richards

Flora Meilleur prepares protein solutions for structural investigation with neutrons. | Courtesy of ORNL Flickr / Jason Richards

Sometimes the right tool can shape the world . . . or even better, touch a life.

That’s true for researchers at the Department of Energy’s Oak Ridge National Laboratory (ORNL) and the University of Tennessee, who recently used one of their tools to discover new truths about Huntington’s disease.

Huntington’s disease is an inherited disorder of body and mind. It begins with a single errant gene, which causes a single misshapen protein (huntingtin), which leads to a devastating series of consequences. Some 1 in 10,000 Americans are affected by Huntington’s, which causes involuntary movements, losses of emotion, dementia and other significant brain impairments. While there are a few treatments, there is no cure.

Everyone carries the huntingtin protein. Scientists aren’t exactly sure what it does, but they believe it plays a role in nerve cells (neurons) in the brain, and know it is critical for life. They also know that misshapen huntingtin proteins pile up inside neurons as the disease progresses, in thin deposits known as fibrils, and believe that the earliest aggregates may be the most toxic.

So researchers at ORNL took a look at the misshapen form of huntingtin aggregates in the earliest stages of disease at the smallest scale so far resolved, the sub-nanoscale level, tenths-of-billionths of a meter. By comparison, a sheet of newspaper is about 100,000 nanometers thick, and a human hair is approximately 80,000 nanometers wide. They used a tool called “Bio-SANS” (Biological Small-Angle Neutron Scattering Instrument), at ORNL’s High Flux Isotope Reactor (HFIR). Bio-SANS – the cornerstone of ORNL’s Center for Structural Molecular Biology – uses neutrons (tiny electrically neutral particles), to study the structure of larger, biologically-important structures like proteins.

This approach has advantages that lead to advances. Using Bio-SANS, researchers can ‘see’ how biological structures look in solutions, their natural state. The tool can also pinpoint the placement of small atoms in great detail, which allows scientists to understand how those structures change over time.

Atomic architecture matters. And through Bio-SANS, ORNL scientists were able to see and study the entire growth curve of the misshapen huntingtin proteins: How their individual components came together, how their toxic aggregates formed, and joined together into fibrils inside the neuron. (Read more about their results in Biophysical Journal.

Knowing the shifting shapes of those noxious structures may allow scientists to devise medicines that prevent them from forming, or counteract their toxic properties. ORNL’s tools are leading to better targets, and perhaps potential treatments. It’s a real return to the taxpayer.

But the full benefit of the tools ORNL scientists are using to study Huntington’s, and other diseases like Alzheimer’s and Parkinson’s, goes far beyond a better balance sheet or a publication in a prestigious scientific journal. It’s the prospect that they’ll contribute to a treatment, or perhaps even a remedy. 

This research was supported by the National Institutes of Health. HFIR and Bio-SANS are supported by the Office of Science.

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