An amino acid answer

Huntington's disease is caused by abnormal coding in the huntingtin gene, but a sequence of 17 amino acids adjacent to that abnormality is under investigation as the cause of that coding anomaly

Kelsey Kaustinen
MORGANTOWN, W. Va.—Huntington's disease is an inherited, progressive neurodegenerative disease that manifests in dementia, cognitive decline and uncontrollable movement. While it was once a relatively rare condition, the Huntington's Disease Society of America (HDSA) notes that “HD is now considered one of the more common hereditary diseases.”
 
A nearby sequence of amino acids could provide answers to the root of this disease, as recent research has shown that a sequence of 17 amino acids, known as N17, has a significant role in modifying the accumulation of the huntingtin protein and, therefore, perhaps the disease's development. Justin Legleiter, associate professor in the C. Eugene Bennett Department of Chemistry at West Virginia University, is leading a team in studying N17, which is known to facilitate the binding of the huntingtin protein to cellular membranes. The team will seek to determine how modifications to the N17 sequence can regulate how the huntingtin protein interacts with specific types of lipids membranes, and is supported by a grant from the National Institutes of Health. Legleiter's co-investigator on this project is Stephen Valentine, assistant professor of chemistry at West Virginia University.
 
Huntington's disease is caused by a mutation in the HTT gene, which codes for the huntingtin protein. According to the Genetics Home Reference page of the National Library of Medicine's website, “The HTT mutation that causes Huntington disease involves a DNA segment known as a CAG trinucleotide repeat. This segment is made up of a series of three DNA building blocks (cytosine, adenine and guanine) that appear multiple times in a row. Normally, the CAG segment is repeated 10 to 35 times within the gene. In people with Huntington disease, the CAG segment is repeated 36 to more than 120 times. People with 36 to 39 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with 40 or more repeats almost always develop the disorder. An increase in the size of the CAG segment leads to the production of an abnormally long version of the huntingtin protein. The elongated protein is cut into smaller, toxic fragments that bind together and accumulate in neurons, disrupting the normal functions of these cells. The dysfunction and eventual death of neurons in certain areas of the brain underlie the signs and symptoms of Huntington disease.”
 
“We don’t have a completely clear picture, but there’s evidence that there may be key interactions between huntingtin and a variety of cellular membranes that are predominately composed of lipids,” Legleiter said.
 
It is hoped that once the details of how huntingtin interacts with cellular membranes are interpreted, it could lead to new therapeutic targets that could combat this disease.
 
“Current estimates are that one in every 10,000 Americans has HD, and more than 250,000 others are at risk of having inherited it from a parent,” HDSA notes on its website. According to the HDSA, symptoms traditionally manifest between the ages of 30 and 50, and worsen over a 10- to 25-year period. There is no cure for the disease, though various medications have seen limited success in offering symptomatic relief for patients.

Kelsey Kaustinen

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