Defective Protein in Huntington’s Linked to Heart Dysfunction in Mouse Study

A key protein in Huntington’s disease has damaging effects on heart function beyond the disease’s devastating neurological impact, according to researchers.

Their study, “Cardiac mTORC1 Dysregulation Impacts Stress Adaptation and Survival in Huntington’s Disease,” was published in the journal Cell Reports.

Huntington’s disease is caused by a mutation in the HTT gene, which leads to the production of a longer-than-normal version of the huntingtin protein. This abnormal protein is then cut short into smaller, toxic fragments, which may clump in neurons and impair their function.

The damaging effects of abnormal huntingtin are felt especially in the brain, resulting in dysfunctional movement, cognition, and mental stability. But other organs may also be affected, including the heart.

Researchers at the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at the Children’s Hospital of Philadelphia used two mouse models of Huntington’s disease to study changes in heart function.

“Heart disease is the second leading cause of death in Huntington’s patients, but its biology remains poorly understood,” Beverly L. Davidson, PhD, the study’s senior author, said in a press release. “Better knowledge of the underlying biology of Huntington’s disease will improve the development of effective therapies.”

It was previously known that mutant huntingtin’s (mHtt) effect on the brain is mediated via a protein complex called mTORC1, which promotes cellular growth and metabolism.

Now, the team found that mice with Huntington’s disease had lower mTORC1 activity as well as smaller hearts than healthy mice. These animals also had a reduced ability to adapt to stress in their hearts, resulting in higher mortality levels.

Restoring mTORC1 function by genetically deleting the defective huntingtin protein allowed mice to better adapt to cardiac stress and live longer.

“These data provide insight into the increased cardiac-related mortality of [Huntington’s] patients,” researchers wrote.

Davidson believes that as current clinical trials in Huntington’s disease are exploring ways to lower the levels of mutant huntingtin, it is important to improve knowledge of disease-associated alterations in organs other than the brain.

While some researchers propose the use of  mTORC1 inhibitors to treat Huntington’s, these results suggest this approach may cause unwanted effects on cardiac function.

“We know from our previous studies that improving mTORC1 functioning may have a protective effect in [Huntington’s], but this would require carefully adjusting the pathway to restore normal mTORC1 levels,” Davidson said.