Rare Disease Report

Study Provides Insight into Increased Cardiac-Related Mortality of Huntington's Disease

MAY 28, 2018
Kristi Rosa
Estimated to affect about 30,000 Americans, Huntington’s disease (HD) is an incurable, autosomal dominant neurodegenerative disease. However, in addition to the disease’s devastating neurological impact, it has also been found to have harmful effects on heart function.

By investigating a key signaling protein in the disease, researchers from the Children’s Hospital of Philadelphia (CHOP) have been able to shed light on the process of the disease, which could potentially help inform future treatments.

“Heart disease is the second leading cause of death in Huntington’s disease patients, but its biology remains poorly understood,” lead study author Beverly L. Davidson, PhD, director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at CHOP admitted in a recent statement. “Better knowledge of the underlying biology of Huntington’s disease will improve the development of effective therapies.”

The progressive brain disorder causes involuntary movements, emotional problems, and cognitive issues and usually appears in a person’s thirties or forties. A defective gene creates repeated copies of huntingtin (HTT). Mutant HTT (mHTT) interrupt cell processes in the body, impairing several organ systems. mTORC1 is a protein complex that encourages cellular growth and metabolism; mHTT disturbs functioning along the mTORC1 pathway.

When it comes to the neurology of HD, mTORC1 is known to be a key player. The study, published in Cell Reports, looked at heart function in mice with HD and found that compared with healthy mice, mice with HD had lower mTORC1 activity; they also had hearts that were smaller normal. Importantly, the investigators noted that mice with the disease were less capable of adapting to stress on their hearts, and thus, had higher stress-associated mortality.

However, after using genetic techniques to take out the mHTT, the investigators were able to activate mTORC1 in the mice with HD, which increased survival and allowed them to adapt to cardiac stress better.

The researchers posit that if the effect that mHTT protein has in humans with HD is similar as to what the investigators saw in the mice, this could explain the heart-related mortality seen in patients. However, more research is needed to confirm this.

“These data provide insight into the increased cardiac-related mortality of HD patients, with cardiac mHTT expression inhibiting mTORC1 activity, limiting heart growth, and decreasing the heart’s ability to compensate to chronic stress,” study authors conclude.
 

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