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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Contact: Natalie Frazin or Stephanie Clipper
301-496-5924
NIH/National Institute of Neurological Disorders and Stroke
13-Oct-2004