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November 29, 2004

UW group blocks formation of toxic protein clumps seen in Huntington’s disease

Researchers at the University of Washington have identified the mechanism for a protein that can protect against formation of the toxic protein clumps seen in Huntington’s disease. Their results appear in the December 2004 issue of the journal Nature Structural & Molecular Biology, now available online through the journal’s Web site, http://www.nature.com/nsmb/.

Many neurodegenerative diseases, such as Huntington’s, Alzheimer’s and Parkinson’s, are characterized by the formation of long protein clumps called amyloid fibrils. For years, scientists believed these fibrils forming in the brain caused neurons to die during the progression of neurodegenerative disorders. However, many researchers now believe that an alternate type of clump, composed of sphere-shaped aggregates that might later combine to form long fibrils, are actually the cause of neurons dying.

Scientists have previously seen such spherical aggregates in other neurodegenerative diseases like Alzheimer’s, but not in Huntington’s disease.

Dr. 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. The researchers found that the huntingtin protein fragment, which causes Huntington’s disease, does form the spherical aggregates that may make the disease so devastating. The group was also able to use a protective substance known as a molecular chaperone to keep the spherical aggregates from forming.

“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 explained.

The conventional wisdom is that chaperones could be used to prevent the formation of fibrillar aggregates. But Muchowski and his colleagues think that’s not exactly the case.

“We think they really know how to cause the formation of good aggregates — the fibrils — instead of bad aggregates, like the spheres,” Muchowski said.

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 Parksinson’s through the same mechanism.


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