New Research Works to Unlock Mystery of Huntington’s Disease

Study finds insights about this little understood condition

Scientist using a microscope

There are few diseases as devastating as Huntington’s disease (HD) – a progressive condition that can cause uncontrollable movement, emotional disturbances and cognitive problems. We know this mysterious condition is encoded in people’s genes, but researchers have yet to unlock exactly how to stop or slow its progression.

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However, new research offers insight about the disease that could lead to better treatments, says Mayur Pandya, DO, a physician in Cleveland Clinic’s Center for Neurological Restoration. Studies seek to understand, at a cellular level, what causes symptoms to manifest and the disease to progress.

Disruption within the brain

Huntingtin is a naturally occurring protein expressed in most cells in our bodies. In each of us, DNA contains “blueprints” for its production.

However, in those with HD, there is a mutation of this protein. As it accumulates in the brain, it becomes toxic — destroying nerve cells in the brain responsible for coordinating thought with body movement (i.e. you think about lifting your finger and you lift it).

The disease can also affect parts of the brain responsible for thinking, affecting people’s memory and their ability to make decisions.

Eventually, a person with HD can find it hard to walk, talk or even swallow. With the progressive disruption within the brain, their personality can become nearly unrecognizable.

“Unlike many better known neurodegenerative diseases that result in dementia, such as Parkinson’s or Alzheimer’s, HD affects people who are much younger,” Dr. Pandya says. “These people, on average, are only 40 years old.”

New research findings

While there is no cure for HD, new research can better explain the peculiar machinery of this disease — the “on” and “off” switches in the cells that cause its symptoms and progression.

New research builds on past findings. One of the first major breakthroughs occurred more than twenty years ago when researchers found the gene responsible for disease toxicity.

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“Since that time, there has been great hope in finding a way to interfere with the production of the toxic protein that leads to the symptoms we see in HD,” Dr. Pandya says.

Research has largely focused on stopping this disease process and medication trials have not shown consistent benefit.

However, scientists from the Florida campus of The Scripps Research Institute recently uncovered a major contributor to HD. The new study shows for the first time a functional connection between huntingtin and a developmentally important gene called mTOR.

This gene integrates signals from multiple pathways, such as growth factors and hormones, to regulate critical cell functions.

Specifically, the scientists found that the huntingtin protein activates signaling by a protein complex known as mTORC1 (mechanistic-target of rapamycin kinase (mTOR) complex 1).

In the mice they studied, when they depleted the huntingtin protein, it reduced activity of mTORC1. When they increased huntingtin protein production, it increased activity of mTORC1 — and caused the mice to prematurely experience HD symptoms.

Finding the ‘off’ switch

Understanding this relationship – what turns the disease “on” or “off” – can help researchers find ways to target treatments for HD. Researchers are exploring if reducing the mTORC1 activation in HD patients, whether through drugs or a low-protein diet, could help prevent the disease process.

“This research is important in that it potentially identifies a step in the process of how the toxic protein in HD causes problems in the brain. Understanding how the toxic protein interacts with other genes and proteins helps us find other opportunities for targeting treatments,” Dr. Pandya says.

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Although this is promising finding, he says we need to keep in mind that the process may be different in humans and that the ability to affect this process in humans, or even tolerate it, may be a challenge.

Future research

“Future HD research will likely involve more invasive interventions to directly target or deliver therapy to the central nervous system (i.e. brain) where the problems in HD are believed to be generated,” Dr. Pandya says.

This could involve the use of biologic treatments and brain stimulation therapies to restore how different parts of the brain communicate with one another.

Dr. Pandya says the efforts will continue as each study finding builds our understanding of HD.

“There has been much effort to understand the factors responsible for the symptoms we see in HD, how the disease causes changes in the brain, and how they influence progression of the disease. Every study brings us one step closer to finding a cure,” Dr. Pandya says.

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