Protein repair defects linked to hidden heart failure

Researchers in the del Monte Lab at the Medical University of South Carolina (MUSC) are the first to observe defects in the protein repair system associated with the peculiar, misfolded protein plaques previously observed in patients with idiopathic dilated cardiomyopathy (IDCM).

IDCM is a heart muscle condition that can go unnoticed until patients are in advanced heart failure. The lab's latest findings, published in the Journal of Molecular and Cellular Cardiology and selected for an editor's choice and journal cover, shows a defect in the repair system of misfolded or damaged proteins. Through a comprehensive study of the three major branches of the repair system, they found changes in key alterations to the repair system machinery in the main branches. These alterations are called post-translational modifications, or PTMs. They concluded that the change in PTMs disrupted the system's ability to respond to misfolded protein stress signals.

Puzzling plaques

When Federica del Monte, M.D., Ph.D., clinician-scientist at MUSC and senior author on the paper, found clusters of misfolded proteins in the heart that eventually led to her landmark 2010 discovery, she was working on a totally separate project.

Then, her experiments showed protein plaques in the heart that resembled those seen in the brain in Alzheimer's disease.

Those same plaques found in the brain were also present in the diseased human hearts, according to del Monte.

She followed up her studies and further linked this discovery to an Alzheimer's gene, connecting Alzheimer's disease and IDCM. [KG4] 

Bringing heart and brain together

Since that discovery, the del Monte Lab has expanded its heart-only focus to include both the heart and brain, bringing cardiologists and neurologists together into its next research steps. This multidisciplinary approach has revealed that the characteristics of IDCM can be seen in the heart even before Alzheimer's is seen in the brain.

"We may use the heart as a window to the brain," del Monte said. 

The reverse is also true. Del Monte's work has introduced IDCM screening in Alzheimer's clinics, advocating for heart ultrasound to detect the telltale enlarged and weakened left ventricle seen in IDCM. Camilla Bacchin, M.D., postdoctoral fellow in the del Monte Lab and co-first author of the paper, hopes that with better screening, earlier treatment could be possible.

"The goal is to diagnose earlier and treat earlier to prevent the worsening of the disease," she said.

The project also reflects the long-term collaboration [MH5] that often drives scientific discoveries. Among the co-authors is Marco Luciani, M.D., Ph.D[MH6] ., a postdoctoral fellow in the del Monte Lab when the project began a decade ago, and now a faculty member at the University of Zurich. Two additional postdoctoral fellows contributed to the work: Luca Trocone, Ph.D., now junior faculty at Brigham and Women's Hospital in Boston, and Cristina Balla, M.D., Ph.D., now faculty at the University of Ferrara in Italy.

Both del Monte and Bacchin emphasized the important contributions of former lab members whose efforts helped to advance the research over many years.

"Their contribution doesn't vanish when they leave the nest," said del Monte.

Their decade-long collaboration, which continued across institutions and continents, ultimately helped them to answer a fundamental question: Why are these plaques forming in the heart?

PTMs perturb protein repair

Because the plaques are made up of misfolded proteins, del Monte and her team set their sights on the system responsible for protein repair. The team examined not only the repair machinery itself but also the PTMs that regulate its activity.

"Often it is not how much protein is present," del Monte said of the system, "but if the changes that activate the proteins are abnormal." 

Bacchin pointed to the PTMs as one of the study's most revealing findings.

"The PTMs seen in disease were primarily causing a shift toward cell death," said Bacchin. In other words, these modifications were causing heart cells to self-destruct. They also found that age and an Alzheimer's gene worsened this effect.

They found that, like Alzheimer's disease, IDCM could be viewed as a protein misfolding disease.

From bench to bedside: what's next?

Looking at the entire repair system, including PTMs, is a requirement for moving forward, explained del Monte. "It needs to be checked in its entirety," she said. Studying the protein repair system at that level of detail may open the door to new potential treatments.

"It is already being tested in cancer research," said del Monte.

Bacchin said she is also looking forward to seeing the results from the bench studies validated in a clinical study, including looking for the molecular changes to identify early biomarkers of disease.

As each discovery continues to reveal overlap between Alzheimer's disease and heart failure, a path is paved toward shared diagnosis and treatment. Interdisciplinary collaborations are taking shape as the del Monte lab coordinates its work with cardiology, neurology and nuclear medicine, among other disciplines. And as the window between the heart and the brain becomes clearer, researchers are uncovering new opportunities for earlier diagnoses and future therapies across both diseases.