The normal huntingtin protein consists of about 3,150 amino acids (which are the building blocks for all proteins). In individuals with Huntington's disease, the mutated protein contains an abnormally long string of a single amino acid repeat; lengthier chains are associated with worse symptoms and earlier onset of the disease. In recent years, however, researchers have begun looking at the effects of other, nearby amino acids in this large protein and in particular, biochemical changes to those amino acids.
In their study, Drs. Steffan and Thompson investigated how a process called phosphorylation affects huntingtin. Phosphorylation is the attachment of chemical tags, known as phosphates, onto the amino acids in a protein. The process occurs naturally and is a way of marking proteins for destruction by cellular waste handling systems. The researchers liken it to putting a sign on a pile of junk that tells the garbage collectors to take it away. Their study shows that phosphorylation of just two amino acids, located at one end of huntingtin, targets the protein for destruction and protects against the toxic effects of the mutant protein.
"Clearance of mutant huntingtin is likely regulated at many levels, but our data establish that these two amino acids are critical," Dr. Steffan said.
Could boosting phosphorylation of those two amino acids reduce the buildup of huntingtin and improve symptoms of the disease? In parallel with the UC Irvine research, Dr. Yang and his team at UCLA were asking that question using an animal model of Huntington's disease. Previously, Dr. Yang had created mice that carry the mutant huntingtin gene. These mice develop symptoms reminiscent of Huntington's disease in humans, including poor coordination, mental changes such as increased anxiety, loss of brain tissue, and accumulation of clumps of huntingtin in brain cells.
|Contact: Gregory Roa|
NIH/National Institute of Neurological Disorders and Stroke