The finding helps to resolve a longstanding debate about the role of these inclusion bodies in HD and other disorders and may help investigators find effective treatments for these diseases. The study was funded primarily by the NIH's National Institute of Neurological Disorders and Stroke (NINDS) and appears in the October 14, 2004, issue of Nature.

Inclusion bodies are common to many neurodegenerative disorders, including HD, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). The role of inclusion bodies in these diseases has long been controversial. Some studies suggest that they may be a critical part of the disease process, while others indicate that they may help protect the cells from toxic proteins or that they are merely bystanders in the disease process.

One problem in identifying how inclusion bodies influence disease is that researchers have been unable to track changes in individual neurons over time. "It was like viewing pictures of a football game and trying to imagine the score," says Steven Finkbeiner, M.D., Ph.D., of the Gladstone Institute of Neurological Disease and the University of California, San Francisco. "Much was happening that we couldn't see."

To overcome this problem, Dr. Finkbeiner and his colleagues wrote a computer program that allows a microscope to match images in a culture dish to images it has stored and to manipulate its controls to look at the same neurons over and over again ” like time-lapse photography. This allowed the investigators to follow changes in a single neuron or a group of neurons over a period of days. They used this automated microscope to study neurons that contained a version of the huntingtin protein that causes HD. The huntingtin was fused to green fluorescent protein, a widely used marker that allows researchers to see where proteins accumulate.

Many neurons with the mutated HD gene died without forming inclusion bodies, the researchers found. The formation of inclusion bodies actually prolonged neurons' survival and lowered their overall risk of death. The rate of cell death was higher in neurons with larger gene mutations, but the death rate for each set of cells remained constant over time.

The researchers also examined the level of mutant huntingtin protein spread throughout the neurons, outside of inclusion bodies. They found that neurons with larger amounts of mutant huntingtin spread throughout the cell died more rapidly than cells with less of this protein. The amount of mutated protein decreased in other parts of the cell when inclusion bodies formed. Taken together, these findings suggest that inclusion bodies lock up mutant huntingtin and keep it from interfering with the rest of the neuron in ways that can trigger cell death.

These findings provide evidence that inclusion bodies in HD, and possibly other neurodegenerative diseases, help neurons cope with toxic proteins and avoid neurodegeneration. Many researchers have been working to develop ways of interfering with inclusion body formation as potential treatments for HD and other disorders. This study suggests that finding ways to remove mutant proteins diffused throughout the cell might be a more effective approach.

"This approach provides a way to connect cellular changes to fate," says Dr. Finkbeiner. The automated microscope system could be applied to sort out many important questions about how cellular changes or abnormalities affect disease, he adds. He and his colleagues are now planning studies to examine the role of proteasomes ” enzyme-filled compartments that break down and recycle proteins ” in HD.

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