For a Rare Brain Disease, Brand New Hope

A change in a single protein could reverse the impacts of Huntington's disease

by Jennifer Fallon | Updated 06 Sep 2016 at 4:04 PM

Huntington’s disease is notorious for being the “cruelest disease known to man.” People who have a mutation of the protein huntingtin 1 or 2 degenerate mentally, physically, and emotionally over a period of 10 to 20 years. The first symptoms — including aggression, jerky movements, and memory loss — usually afflict patients just before they turn 30, and carriers of the gene have a 50-percent chance of passing it onto their kids.

The disease is always fatal.

This could be a promising beginning in the fight for brain health.

But Dr. Steve Finkbeiner and his team of researchers at the Gladstone Institutes in San Francisco recently discovered they can make small changes to the huntingtin protein and see big results. The mutated protein folds incorrectly, making it almost impossible for neurons to eliminate. The buildup causes immense damage, similar to the accumulation of plaques in Alzheimer’s.

The researchers altered the protein by adding a simple molecule to it — a phosphate group. This process, called phosphorylation, has proven effective at turning off protein enzymes and modifying their function. Not only did this process make the protein less toxic, it also made it easier for the neurons to get rid of it — thus minimizing the buildup and damage responsible for Huntington’s.

When the scientists tried this out in a mice model, they saw promising results. The mice were almost indistinguishable from the other mice during simulations.

“I was shocked at the profound effect phosphorylation had on the Huntington’s model mice,” said Dr. Ian Kratter, an author on the study, in a media release. The normal progression of Huntington’s begins in the reward center of the brain, and researchers found that the mice were protected from the neuron death in this area of the brain as well.

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Dr. Finkbeiner told LifeZette it will be a while before this discovery could be used for treatment in humans. “The discovery [of] identifying a site on the huntingtin protein itself has a really beneficial effect on the deficits that the animals develop. It’s still going to be a number of steps before we can develop a drug that can target that site,” he said.

Huntington's Disease
  • Every child of a parent with HD has a 50/50 chance of carrying the faulty gene. Today, there are some 30,000 symptomatic Americans and more than 200,000 at risk of inheriting the disease.

Scientists do not fully understand the cellular pathways that signal protein elimination. But the study shows that phosphate groups in certain areas of the protein could be connected to that process.

Dr. Francis Collins at the National Institutes of Health explained in a statement how protein elimination is vital to brain health: “Even though neurodegenerative diseases have varied roots — and affect distinct cell types in different brain regions — they do share something in common. In most of these disorders, we see some type of toxic protein accumulating in the brain. It’s as if the brain’s garbage disposal system is blocked, letting the waste pile up. In Huntington’s disease, huntingtin is the disease-causing protein. In spinocerebellar ataxia, it’s the ataxins. In Alzheimer’s, it’s beta-amyloid; in Parkinson’s, it’s α-synuclein. When garbage builds up in your kitchen, it’s a bad situation. When it’s in your brain, the consequences are deadly.”

If Dr. Finkbeiner’s team discovers a way to trigger the brain’s garbage disposal system, it could have big implications — not only for Huntington’s but for other degenerative diseases too. Huntington’s is a relatively rare disease, affecting about 30,000 American families. Alzheimer’s, however, currently affects 5.4 million families. Clinical trials involving humans are still in the future. But this could be a promising beginning in the fight for brain health.

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