Turning Off Huntington’s Disease

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The diagnosis of Huntington’s disease — usually in middle age as most patients learn they might carry the genetic mutation when one of their parents gets sick — dictates an unalterable course that ends in death within a decade or two.

First identified in 1842 and accurately described by George Huntington 30 years later, Huntington’s affects one out of 10,000 Americans, primarily those of Western European descent. Although its genetic characteristics and symptoms — starting with jerky movement and continuing into dementia — are well documented, researchers have been baffled by the precise way in which the genetic mutation sets the progression of the disease in motion.

Although the precise gene that produces the mutated protein that leads to Huntington’s was identified in 1993, researchers have not been able to develop any meaningful treatment toward a cure or even for the symptoms of the disease. That the mutant protein behind the disease can be found all over the human body makes the effort even harder.

However, scientists at the University of California, Los Angeles, have pinpointed the molecular mechanism responsible for switching on the gene’s ability to unleash the disease — in mice. This discovery also revealed a method that prevents the gene from completing its dastardly mission. The team’s work was published late last month in the journal Neuron.

Dr. X. William Yang of the Semel Institute of Neuroscience and Human Behavior at UCLA was the lead author of the study. Yang said their approach was based on prior studies by other researchers and focused on how cells use a chemical process called phosphorylation — adding a phosphate molecule to the protein — to control how proteins function.

But rather than working on the portion of the protein that was mutated, phosphorylation, in this case, modified a part of the protein that wasn’t (although it was next to the long string of amino acids that formed the mutation).

“We are actually the first lab to test [the] hypothesis,” Yang said.

Working with two sets of mice carrying the human form of the genetic mutation, the team mimicked phosphorylation on one set, and prevented it on the other. In the former, the experiment deactivated the protein’s ill effect — preventing the lab mice from developing symptoms of Huntington’s.

“This [finding] can stimulate new research in this area,” Yang said. In fact, co-authors of the Neuron paper from the University of Pittsburgh and from University of California, Irvine, have studied other aspects of phosphorylation on the mutant protein, preventing it from clumping and helping the body dispose of it instead of letting it build up in neurons.

Yang said the future now holds the promise of discovering a cure. He said Huntington’s disease is one of the most common neurodegenerative disorders and is purely genetic, “but we are hoping that the lessons we learn from studying Huntington’s disease could be applicable for studying other neurodegenerative disorders that are not purely genetic, like ALS or even Parkinson’s.”

A test was developed to identify who may be carrying that mutated gene even before any symptoms occur. But the issue of whether the children of a parent with Huntington’s should actually take the genetic test has been controversial, mostly because of the absence of effective treatment. Each child of such a parent has a 50/50 chance of carrying the gene.

The UCLA study was funded by the Hereditary Disease Foundation and National Institute of Neurological Disorders and Stroke.

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