Molecular origin of neurodegenerative disorders uncovered

These neurodegenerative diseases 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 and include Huntington’s and spinobulbar muscular atrophy. Excessive polyglutamine expansion is thought to be a key factor in disease etiology.

The researchers sought to determine why a correlation exists between polyglutamine expansion length and nerve cell death and disease. They hypothesized that expansion of glutamines results in alternative structures forming within the protein that compete with its normal structure and function.

Researchers at the University of North Carolina (UNC) used computer simulations to mimic polyglutamine behavior. The 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. The new goal of research will be 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,” said Dr Nikolay Dokholyan, assistant professor of biochemistry and biophysics at UNC.