NEW YORK (GenomeWeb) – University of Florida Health researchers have discovered that the gene that causes the fatal disorder Huntington's disease produces a "cocktail" of mutant proteins that accumulate in the brain.
Huntington's disease is an inherited disorder that affects about 30,000 people in the United States and poses inherited risks for 200,000 people, according to the Huntington's Disease Society of America. The disease, caused when the huntingtin (HTT) gene produces too many copies of CAG, damages nerve cells and causes parts of the brain to deteriorate, leading to uncontrolled movements and both behavioral and cognitive problems. There is no cure and no way to stop the disease's progression, though medications can treat some symptoms.
The findings are significant because these newly identified mutant proteins kill neurons and build up in the regions of the brain that are most affected by the disease, Laura Ranum, director of the UF Center for Neruogenomics and a professor in the department of molecular genetics and microbiology at the UF College of Medicine, said in a statement.
To reach their conclusions, the researchers examined the brains of 12 deceased adult and juvenile patients with Huntington's disease. In addition to the known protein, HTT polyGIn-expansion protein, they found novel homopolymeric expansion proteins (polyAla, polySer, plyLeu, and polyCys) accumulated in the deceased patients' brains.
Researchers found that the CAG repeat mutation can undergo a process known as repeat associated non-ATG (RAN) translation, which produced the four novel repeat proteins that accumulated in the patients' brains. 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. The four proteins are also toxic to neurons.
Finding these novel RAN proteins in degenerated areas of the brain that were negative for the previously known mutant Huntington protein was crucial to linking them to the disease, Monica Bañez-Coronel, a postdoctoral associate and the first author of the journal article, said in a statement.
Knowing that rogue proteins are implicated in Huntington's disease is just the first step. Ranum said further research is needed, and it will be important to understand how these proteins are being made without the normal cellular signals and if strategies to block their production can be developed. In addition to the possibility of new therapies, detecting these proteins may be useful for predicting the disease's onset, as well as its progression and treatment responses, the researchers said.