Researchers at the University of North Carolina ( UNC ) at Chapel Hill School of Medicine points to the possible molecular origin of at least nine human diseases of nervous system degeneration.

These neurodegenerative diseases, including Huntington's disease, share an abnormal deposit of proteins inside nerve cells.
This deposition of protein results from a kind of genetic stutter within the cell's nucleus asking for multiple copies of the amino acid glutamine, a building block of protein structure.
These disorders are collectively known as polyglutamine diseases.
Along with Huntington's, these diseases include spinobulbar muscular atrophy; spinocerebellar ataxia types 1, 2, 3, 6, 7 and 17; and dentatorubral-pallidoluysian atrophy, or Haw River Syndrome.

Haw River Syndrome is a genetic brain disorder first identified in 1998 in five generations of a family having ancestors born in Haw River.
The disorder begins in adolescence ( between ages 15 and 30 years ) and is characterized by progressive and widespread damage to brain function, leading to loss of coordination, seizures, paranoid delusions, dementia and death within 15 to 20 years.

Researchers are uncertain if protein deposition causes nerve cells to deteriorate and die. However, studies show that the greater the number of glutamine repeats in a protein above a certain threshold, the earlier the onset of disease and the more severe the symptoms. This result suggests that abnormally long glutamine tracts render their host protein toxic to nerve cells.

" Polyglutamine expansion greater than 35 to 40 repeats is definitely a key player in disease etiology and, perhaps, cell death," said Nikolay V. Dokholyan at UNC.

In their study, Dokholyan and UNC co-authors sought to determine why a correlation exists between polyglutamine expansion length and nerve cell death, or disease. They hypothesized that expansion of glutamines results in alternative structures forming within the protein that compete with its normal structure and function.

" As a result, the protein cannot function properly and, possibly, aggregates," Dokholyan said. In other words, an abnormally long sequence of glutamines might take on a shape that prevents the host protein from "folding" or coiling into its functional three-dimensional shape. All protein molecules are simple unbranched chains of amino acids; proper folding into an intricate shape enables these molecules to perform their biological function.

Researchers used computer simulations to mimic polyglutamine behavior. The UNC study showed that when the number of glutamine repeats exceeds a critical value, the glutamines tend to take on a specific shape in the protein called a beta helix. Moreover, the tendency to form a beta helix increases as glutamine tract length becomes longer.

" In our simulations, when the length is 25 glutamines, no beta helix forms. At 45, a large majority show beta helix formation," Dokholyan said. "And it appears that 37 glutamines marks a transition, as only a small number of beta helices are formed."

Dokholyan said one of his team's goals is to find a way to inhibit the formation of protein aggregates.

" If we understand the mechanism and the structure, it may become possible to develop ways, including new small molecule drugs, that would interfere with the process of aggregation.

" Our philosophy in general has been that many diseases have underlying molecular etiology. And if something goes wrong at the organism level, it also goes wrong at the molecular level. We try to understand the dynamics and the change in structure that occurs in these molecules with the hope of uncovering their toxicity to the cell."

Source: University of North Carolina School of Medicine, 2005


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