Huntington disease (HD) is an incurable, inherited neurological disorder caused by the mutant Huntingtin gene, which produces a mutant form of Huntingtin protein (mHTT). In addition to creating the profound neurological impacts of HD, the mHTT protein also impairs other organ systems, and new research, published in Cell Reports, suggests that the protein may play a role in cardiac-related mortality in patients with HD.
Huntington disease (HD) is a rare, incurable, inherited neurological disorder caused by the mutant Huntingtin gene, which produces a mutant form of Huntingtin protein (mHTT). In addition to creating the profound neurological impacts of HD, the mHTT protein also impairs other organ systems, and new research, published in Cell Reports, suggests that the protein may play a role in cardiac-related mortality in patients with HD.
Heart disease is the second leading cause of death in patients with HD, though the phenotype is poorly understood. The authors of the paper explain that among the key regulators of heart size and stress response is the mechanistic Target of Rapamycin complex 1 (mTORC1), which promotes cellular growth and metabolism. In a mouse model of HD, researchers observed that mTORC1 activity was decreased, and that HD mice had hearts that were smaller than those of non-HD mice.
Hypothesizing that, if mHTT expression dysregulates mTORC1, reducing mHTT levels should ameliorate that phenotype, they treated pre-symptomatic HD mice with miRNA targeting HTT, and found that the treated mice had a robust increase in the mTORC1 targets, ribosomal protein S6 and initiation factor 4E binding protein 1. These results, say the authors, suggest that cardiac mHTT is key to mTORC1 inhibition.
They also found that HD mice had worse adaptation to cardiac stress; with stress, HD mice had a sustained increase in heart rate and contractility, but did not undergo the same hypertrophy that allowed non-HD mice to have continued function and survival. When the researchers selectively activated mTORC1 in HD mice, the mice regained their adaptive cardiac stress response and displayed significantly less morality over the course of the study.
The researchers say that these findings suggest that mHTT’s impact on mTORC1 impairs the ability of cardiomyocytes to respond to stressors, which may underlie the etiology of heart disease—induced death in patients with HD .
“If the mHTT protein has a similar effect on human hearts as in the mice, it may explain the heart-related mortality” seen in patients with HD, said Beverly L. Davidson, PhD, one of the study’s authors, in a statement. She added that, given that there are currently clinical trials of HTT-lowering therapy in patients with HD, it is important to better understand how HD affects organs outside the central nervous system.
“We know from our previous studies that improving mTORC1 functioning may have a protective effect in HD, but this would require carefully adjusting the pathway to restore normal mTORC1 levels,” said Davidson.
Child DD, Lee JH, Pascua CJ, Chen YH, Monteys AM, Davidson BL. Cardiac mTORC1 dysregulation impacts stress adaptation and survival in Huntington’s disease. Cell Reports. 2018;23(4):1020-1033. doi: 10.1016/j.celrep.2018.03.117.