Researchers have made a new discovery about Huntington’s disease, showing that the gene that causes the fatal disorder makes an unexpected “cocktail” of mutant proteins that accumulate in the brain.
The findings are significant because these newly identified mutant proteins kill neurons and build up in regions of the brain that are most affected by the disease. The findings were published in the journal Neuron.
The researchers examined the brains of 12 deceased adult and juvenile patients with Huntington’s disease. They found novel proteins that were abundant in areas of patients’ brains that showed cell death, neuronal loss and other signs of disease, including neuroinflammation.
Along with a protein already implicated in Huntington’s disease, the researchers found four proteins that also contribute to the disease pathology. The disease stems from a genetic mutation in the Huntingtin gene that produces too many copies of a DNA segment known as CAG, which gives rise to a longer Huntingtin protein with toxic effects. However, researchers found that this DNA repeat mutation can undergo a process known as repeat associated non-ATG (RAN) translation, producing four additional damaging repeat proteins that accumulate in the brain. This was a surprise to the researchers because these RAN proteins are made without a signal in the genetic code that was previously thought to be required for protein production. Each of the four RAN proteins contains long repeats of certain single protein building blocks, or amino acids.
Finding these novel RAN proteins in degenerated areas of the brain that were negative for the previously known mutant Huntingtin protein was crucial to linking them to the disease, said Monica Bañez-Coronel, Ph.D., a postdoctoral associate and the first author of the journal article.
Source: University of Florida