New research from the University of North Carolina at Chapel Hill School of Medicine points to the possible molecular origin of at least nine human diseases of nervous system degeneration.
The findings are currently in PLoS Computational Biology, an open-access journal published by the Public Library of Science (PloS) in partnership with the International Society for Computational Biology.
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, N.C. 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.
Scientists 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 Dr. Nikolay V. Dokholyan, assistant professor of biochemistry and biophysics at UNC.
In their new 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.