New Clues To The Cause Of Huntington's And Other Neurological Diseases

By Justin Reedy

A shadowy figure stalks the brain, killing off neurons, in turn causing its victim to slowly lose nervous system function. For years, scientists thought they had the dangerous culprit behind neurodegenerative disease in their sights.

But new evidence is pointing at different perpetrators.

The conventional wisdom on neurodegenerative diseases has been that defective proteins clump together in brain cells, and over time those clumps cause neurons to die.

However, research into the mechanisms of those diseases has started to call that theory into question.

Scientists know that neurodegenerative diseases like Huntington's, Alzheimer's, and Parkinson's can lead to the formation of two types of long protein clumps: amyloid fibrils, and inclusion bodies. New research has shown that the clumps, formerly believed to be the culprit behind the death of neurons, may actually be formed to protect brain tissue.

The real culprit may instead be sphere-shaped protein aggregates that later combine to form fibrils.

Both the fibrils and spherical aggregates are formed from misshapen proteins associated with the particular disease. In the case of Huntington's disease, that means the mutant huntingtin protein.

Scientists at the Gladstone Institute of Neurological Disease, an affiliate of the University of California-San Francisco, used a specially designed microscope to watch the progression of neurons infected with the mutant huntingtin protein. They found that when the proteins come together and form inclusion bodies, those structures are actually a natural coping mechanism that may help protect neurons. Their results appeared on the cover of the journal Nature on Oct. 14, 2004.

The findings indicate that the mutant huntingtin protein is harming neurons at a stage other than as inclusion bodies. Researchers believe that could also be the case for other neurodegenerative diseases like Alzheimer's and Parkinson's.

These results "will help us to better focus efforts to identify the mechanisms by which the huntingtin protein causes Huntington's and may add to the understanding of other neurodegenerative disorders," says Steven Finkbeiner, who led the study. Finkbeiner is an assistant investigator at the Gladstone Institute and assistant professor of neurology and physiology at UCSF.

Other researchers have started to look for ways to protect neurons from what may be the real culprit. At the University of Washington in Seattle, scientists have focused on sphere-shaped aggregates that many believe may actually be the cause of neurons dying.

The spherical aggregates are an intermediate step in the progression of Huntington's disease. They later join together to form amyloid fibrils. Some researchers think that before that happens, the aggregates are killing off neurons.

Paul Muchowski, assistant professor of pharmacology at the UW, led a group of researchers who examined the Huntington's protein clumping process at the molecular level. They used biochemical analysis and an imaging technique known as atomic-force microscopy to watch the process in a lab environment.

They were able to see for the first time that the huntingtin protein does form the toxic spherical aggregates, which were previously seen in other diseases like Alzheimer's. The group was also able to use a protective substance known as a molecular chaperone to keep the spherical aggregates from forming. Their results appear in the December 2004 issue of the journal Nature Structural & Molecular Biology.

"What the chaperones do is stabilize the native structure of the proteins, not allowing them to form these spheres, but surprisingly the fibrils still form," Muchowski explains. "We think the chaperones know how to cause the formation of good aggregates&ndashthe fibrils–instead of bad aggregates, like the spheres."

If it turns out that spherical aggregates are the culprits behind neurons dying, then chaperones could hold the key to limiting or preventing their effects in Huntington's and other neurodegenerative diseases.

Researchers are working to develop a drug that could boost the production of chaperones in the nervous system, helping the body protect itself from the disease.

Muchowski's results could also impact other research on treatments for Huntington's disease. Many of those treatments try to prevent the formation of fibril aggregates. However, that approach may hurt in the long run if spherical aggregates are still able to form and damage brain tissue. Muchowski is now trying to determine if the chaperones protect against Alzheimer's and Parkinson's through the same mechanism.

Justin Reedy is a science writer/editor for the University of Washington Office of Health Sciences News and Community Relations, and is working towards a graduate degree in technical communication from the UW.