Does an Impaired Biological Pathway Help Explain Heart Problems in Huntington’s Disease?

May 1 2018

Does an Impaired Biological Pathway Help Explain Heart Problems in Huntington’s Disease?

The Findings:

Researchers gained new insights into the heart problems that are the second leading cause of death in patients with Huntington’s disease (HD). An incurable, inherited disease with progressive loss of brain cells and motor function, HD occurs when a defective gene produces repeated copies of a protein called huntingtin, or HTT. The mutant HTT (mHTT) protein disrupts multiple fundamental cellular processes along the mTORC1 pathway that promotes cell growth and metabolism. The study team described how decreased mTORC1 activity contributed to the development of heart disease with stress in mouse models of HD. By restoring cardiac mTORC1 activity, the researchers improved the animals’ heart function and survival over the course of the study.

Why it matters:

While researchers already know that mTORC1 function plays a role in HD’s devastating neurological impact, they want to better understand how this important biological pathway impairs multiple organ systems. Data from this study shed light on how heart problems reflect broader effects of the abnormal protein in HD, and the findings will help to inform the development of effective therapies. For example, some researchers propose using mTORC1 inhibitors to treat HD, but the new study suggests that this approach could cause unintended effects on cardiac function.

Who conducted the study:

Beverly Davidson, PhD, director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (CCMT) at Children’s Hospital of Philadelphia, where she is an expert on gene therapy for inherited brain disorders, led the study. Dr. Davidson also is a professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania. The study team included first author Daniel Child, MD, PhD, and other scientists from the CCMT, along with colleagues from the University of California, Los Angeles.

How they did it:

The study team compared mouse models of HD to healthy mice. Their results showed that mTORC1 activity was lower in HD mice, they had smaller than normal hearts, they were less able to adapt to stress on their hearts, and they had higher mortality from that stress. When the researchers used genetic techniques to knock down the mHTT protein and restore cardiac mTORC1 activity, the mice were better able to adapt to cardiac stress.

Quick thoughts:

“If the mHTT protein has a similar effect on human hearts as in the mice, it may explain the heart-related mortality seen in HD patients,” Dr. Davidson said.

What’s next:

Future studies on human HD heart tissues will help researchers identify the possible consequences of the impaired mTORC1 activity observed in HD mouse model hearts. Given that there are currently clinical trials of HTT-lowering therapy in patients with HD, it is important for researchers to know how the underlying biology of HD affects organs outside the central nervous system.

Where the study was published:

The article appeared in Cell Reports.

Where to learn more:

Visit the Davidson Laboratory website. Learn more about previous studies about mTORC1 dysregulation related to HD. And read the full press release about the current study.