Study Points To Molecular Origin Of Neurodegenerative Disorders, Including Huntington's Disease

The findings are currently in PLoS Computational Biology, anopen-access journal published by the Public Library of Science (PloS)in partnership with the International Society for ComputationalBiology.

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

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

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

"Polyglutamine expansion greater than 35 to 40 repeats isdefinitely a key player in disease etiology and, perhaps, cell death,"said Dr. Nikolay V. Dokholyan, assistant professor of biochemistry andbiophysics at UNC.

In their new study, Dokholyan and UNC co-authors sought to determinewhy a correlation exists between polyglutamine expansion length andnerve cell death, or disease. They hypothesized that expansion ofglutamines results in alternative structures forming within the proteinthat 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 longsequence of glutamines might take on a shape that prevents the hostprotein from "folding" or coiling into its functional three-dimensionalshape. All protein molecules are simple unbranched chains of aminoacids; proper folding into an intricate shape enables these moleculesto perform their biological function.